1,4-disubstituted imidazole derivative

ABSTRACT

The present invention provides a 1,4-disubstituted imidazole derivative of formula (1′) wherein ring Q 1  is optionally-substituted C 6-10  aryl group, etc.; R 1  and R 2  are independently hydrogen atom, etc.; W 1  is optionally-substituted C 1-4  alkylene group; W 2  is —NR 3a C(O)— wherein R 3a  is hydrogen atom or C 1-6  alkyl group, etc.; ring Q 2  is 5- to 10-membered heteroaryl group, etc.; W 3  is optionally-substituted C 1-4  alkylene group, etc.; n is 1, 2, 3, 4, or 5; R 4  is independently halogen atom, optionally-substituted C 1-6  alkyl group, etc.; R 5  is hydroxy group, etc.; and a pharmacologically acceptable salt thereof, which have a potent inhibitory effect on the sphere-forming capacity of cancer cells and are useful as an orally-available anti-tumor agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No. PCT/JP2016/068423, filed on Jun. 21, 2016, which claims the benefit of Japanese Application No. 2015-125174, filed on Jun. 22, 2015, the entire contents of each are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a pharmaceutically-useful 1,4-disubstituted imidazole derivative including a pharmaceutically acceptable salt thereof, and an anti-tumor agent comprising it as an active ingredient.

BACKGROUND ART

Conventional cancer treatments are sometimes not expected to bring in meaningful survival effects even if they can induce the regression of tumors, because of the persistent proliferation of malignant tumors, the metastasis or recurrence of cancer, and the resistance to anti-tumor agents. These days, it has been suggested that cancer stem cell (hereinafter referred to as “CSC”) is one of the causes of the failure, which is closely involved in the factors such as the persistent proliferation of malignant tumor. CSCs have been identified in almost all types of major cancers in human such as breast cancer, colon cancer, lung cancer, and hematological malignancy (Non-Patent Document 1). Also, CSCs can be greatly different in the biological feature from normal cancer cells which differentiate from CSCs, and thus the development of an anti-tumor agent whose target is CSCs is expected to lead to a new strategy for cancer treatments (Non-Patent Document 2).

One of the features in CSCs is the self-renewal ability (Non-Patent Document 3). Reliable methods established for measuring the self-renewal ability of cells include, for example, a method for measuring the sphere-forming ability of cancer cells in non-adherent condition in the absence of serum (Non-Patent Document 4).

Non-Patent Document 5 discloses that PF-03084014 having an N-imidazolylamide scaffold can inhibit CSCs to exhibit an anti-cancer effect. However, Non-Patent Document 5 does not disclose the compound of formula (1′) of the present invention.

PRIOR ART DOCUMENTS Non-Patent Documents

-   Non-Patent Document 1: Boman et al., Journal of Clinical Oncology     26(17): 2795-2799. 2008 -   Non-Patent Document 2: Lobo et al., Annu Rev Cell Dev Biol 23:     675-99. 2007 -   Non-Patent Document 3: Al-Hajj et al., Oncogene 23(43): 7274-82.     2004 -   Non-Patent Document 4: Ponti et al., Cancer Res 65(13): 5506-11.     2005 -   Non-Patent Document 5: Zhang et al., Stem Cells Translational     Medicine 2: 233-242. 2013

SUMMARY OF INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide a novel anti-tumor agent whose target is CSCs which are thought to be closely involved in the persistent proliferation of malignant tumor, the metastasis or recurrence of cancer, and the resistance to anti-tumor agents.

Means for Solving the Problems

The present inventors have extensively studied to reach the above object, and then have found that a compound of the following formula (1′) or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the present compound”, as necessary) has a potent inhibitory effect on the sphere-forming ability of cancer cells and is highly useful as a novel anti-tumor agent. Based upon the new findings, the present invention has been completed.

The present invention provides inventions described below.

[1] A compound of formula (1′):

or a pharmaceutically acceptable salt thereof, wherein ring Q¹ is optionally-substituted C₆₋₁₀ aryl group, optionally-substituted C₃₋₁₀ cycloalkyl group, or optionally-substituted 5- to 10-membered heteroaryl group;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W¹ is optionally-substituted C₁₋₄ alkylene group;

W²-Q² is —NR^(3a)C(O)-Q², —NR^(3a)C(O)O-Q², —NR^(3a)C(O)OCH₂-Q², —NR^(3a)C(O)NR^(3b)-Q², —NR^(3a)C(O)NR^(3b)CH₂-Q², —NR^(3a)C(O)CH₂O-Q², —NR^(3a)C(O)CH₂-Q², —NR^(3a)C(O)CH₂CH₂-Q², —C(O)NR^(3a)-Q², —C(O)NR^(3a)CH₂-Q², —C(O)NR^(3a)CH₂CH₂-Q², or —NR^(3a)C(O)—CR^(3c)═CR^(3d)-Q² wherein R^(3a) and R^(3b) are independently hydrogen atom or C₁₋₆ alkyl group; and R^(3c) and R^(3d) are independently hydrogen atom, fluorine atom, or C₁₋₆ alkyl group;

ring Q² is 5- to 10-membered heteroaryl group;

W³ is optionally-substituted C₁₋₄ alkylene group, optionally-substituted C₃₋₄ alkenylene group, or optionally-substituted C₃₋₄ alkynylene group;

n is 1, 2, 3, 4, or 5;

R⁴ is, independently when two or more exist, hydrogen atom, halogen atom, optionally-substituted C₁₋₆ alkyl group, optionally-substituted C₁₋₆ alkoxy group, optionally-substituted C₃₋₁₀ cycloalkyl group, optionally-substituted C₂₋₆ alkenyl group, optionally-substituted C₂₋₆ alkynyl group, cyano group, optionally-substituted C₁₋₆ alkyl-carbonyl group, optionally-substituted C₁₋₆ alkylsulfonyl group, optionally-substituted C₁₋₆ alkoxy-carbonyl group, optionally-substituted C₁₋₆ alkyl-carbonylamino group, optionally-substituted C₁₋₆ alkylsulfonylamino group, optionally-substituted C₁₋₆ alkoxy-carbonylamino group, optionally-substituted C₁₋₆ alkyl-carbonyloxy group, optionally-substituted amino group, optionally-substituted aminocarbonyl group, optionally-substituted aminosulfonyl group, optionally-substituted 5- or 6-membered cyclic amino group, optionally-substituted 5- or 6-membered cyclic aminocarbonyl group, nitro group, or carboxyl group;

when R⁴ and W³ are attached to the adjacent carbon atoms on ring Q², they may be combined with the carbon atoms to form 5- to 8-membered cycloalkane ring; and

R⁵ is

(1) hydroxy group, (2) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, C₁₋₆ alkoxy, and C₆₋₁₀ aryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, (3) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups, or (4) C₁₋₆ alkyl-carbonylamino group wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 halogen atoms. [2] A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein ring Q¹ is optionally-substituted C₆₋₁₀ aryl group, optionally-substituted C₃₋₁₀ cycloalkyl group, or optionally-substituted 5- to 10-membered heteroaryl group;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W¹ is optionally-substituted C₁₋₄ alkylene group;

W²-Q² is —NR^(3a)C(O)-Q², —NR^(3a)C(O)O-Q², —NR^(3a)C(O)OCH₂-Q², —NR^(3a)C(O)NR^(3b)-Q², —NR^(3a)C(O)NR^(3b)CH₂-Q², —NR^(3a)C(O)CH₂O-Q², —NR^(3a)C(O)CH₂-Q², —NR^(3a)C(O)CH₂CH₂-Q², —C(O)NR^(3a)-Q², —C(O)NR^(3a)CH₂-Q², or —C(O)NR^(3a)CH₂CH₂-Q² wherein R^(3a) and R^(3b) are independently hydrogen atom or C₁₋₆ alkyl group;

ring Q² is 5- to 10-membered heteroaryl group;

W³ is optionally-substituted C₁₋₄ alkylene group, optionally-substituted C₃₋₄ alkenylene group, or optionally-substituted C₃₋₄ alkynylene group;

n is 1, 2, 3, 4, or 5;

R⁴ is, independently when two or more exist, hydrogen atom, halogen atom, optionally-substituted C₁₋₆ alkyl group, optionally-substituted C₁₋₆ alkoxy group, optionally-substituted C₃₋₁₀ cycloalkyl group, optionally-substituted C₂₋₆ alkenyl group, optionally-substituted C₂₋₆ alkynyl group, cyano group, or optionally-substituted amino group;

when R⁴ and W³ are attached to the adjacent carbon atoms on ring Q², they may be combined with the carbon atoms to form 5- to 8-membered cycloalkane ring; and

R⁵ is

(1) hydroxy group, (2) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, C₁₋₆ alkoxy, and C₆₋₁₀ aryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, (3) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups, or (4) C₁₋₆ alkyl-carbonylamino group wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 halogen atoms. [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof wherein ring Q¹ is (1) C₆₋₁₀ aryl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) C₆₋₁₀ aryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(f) 5- or 6-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(g) C₆₋₁₀ aryloxy which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(h) hydroxy,

(i) amino which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(j) aminocarbonyl wherein the amino moiety thereof may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(k) C₁₋₆ alkoxycarbonyl wherein the alkoxy moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(l) C₁₋₆ alkyl-carbonyl wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(m) C₁₋₆ alkylsulfonyl wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(n) C₁₋₆ alkyl-carbonylamino wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(o) C₁₋₆ alkylsulfonylamino wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(p) C₁₋₆ alkoxy-carbonylamino wherein the alkoxy moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(q) C₁₋₆ alkyl-carbonyloxy wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(r) aminosulfonyl wherein the amino moiety thereof may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups, and

(s) C₃₋₁₀ cycloalkyl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(2) C₃₋₁₀ cycloalkyl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of (a) to (s) defined in the above (1), or (3) 5- to 10-membered heteroaryl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of (a) to (s) defined in the above (1);

W¹ is C₁₋₄ alkylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy;

W³ is

(1) C₁₋₄ alkylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (2) C₃₋₄ alkenylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or (3) C₃₋₄ alkynylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms; and

R⁴ is, independently when two or more exist,

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₃₋₁₀ cycloalkyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (6) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (7) C₂₋₆ alkynyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (8) cyano group, or (9) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups;

when R⁴ and W³ are attached to the adjacent carbon atoms on ring Q², they may combined with the carbon atoms to form 5- to 8-membered cycloalkane ring.

[4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof wherein ring Q¹ is (1) phenyl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) phenyl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(f) 5- or 6-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, and

(g) phenoxy which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(2) C₃₋₇ cycloalkyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of (a) to (g) defined in the above (1), or (3) pyridyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of (a) to (g) defined in the above (1). [5] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof wherein ring Q¹ is phenyl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms, and

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 halogen atoms.

[6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof wherein W¹ is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 halogen atoms. [7] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof wherein W²-Q² is —NR^(3a)C(O)-Q², —NR^(3a)C(O)CH₂O-Q², or —C(O)NR^(3a)-Q² wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl group. [8] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof wherein W²-Q² is —NHC(O)-Q² or —C(O)NH-Q². [9] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof wherein ring Q² is pyridyl group, pyrimidyl group, pyridazyl group, pyrazyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, or quinoxalinyl group. [10] The compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof wherein ring Q² is pyridyl group, pyridazyl group, pyrazyl group, oxazolyl group, thiazolyl group, isoxazolyl group, or quinolinyl group. [11] The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof wherein W³ is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy; and R⁵ is hydroxy group, or C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy. [12] The compound according to claim 1 which is represented by formula (1a′):

or a pharmaceutically acceptable salt thereof, wherein ring Q^(1a) is phenyl group, pyridyl group, or cyclohexyl group;

m is 1, 2, 3, 4, or 5;

R¹¹ is, independently when two or more exist,

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ (alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms, or (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W^(1a) is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 halogen atoms;

W^(2a)-Q^(2a) is —NR^(3a)C(O)-Q^(2a), —NR^(3a)C(O)CH₂O-Q^(2a), —C(O)NR^(3a)-Q^(2a), or —NR^(3a)C(O)—CH═CH-Q^(2a) wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl group;

ring Q^(2a) is 5- or 6-membered heteroaryl group;

W^(3a) is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy;

R¹² and R¹³ are independently

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₃₋₁₀ cycloalkyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (6) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (7) C₂₋₆ alkynyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (8) cyano group, or (9) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups;

when R¹³ and W^(3a) are attached to the adjacent carbon atoms on ring Q², they may combined with the carbon atoms to form 5- or 6-membered cycloalkane ring; and

R¹⁴ is hydroxy group, or C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy.

[13] The compound according to claim 1 which is represented by formula (1a):

or a pharmaceutically acceptable salt thereof, wherein ring Q^(1a) is phenyl group, pyridyl group, or cyclohexyl group;

m is 1, 2, 3, 4, or 5;

R¹¹ is, independently when two or more exist,

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms, or (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

R¹ and R² are independently hydrogen atom, halogen atom, or C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W^(1a) is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 halogen atoms;

W^(2a)-Q^(2a) is —NR^(3a)C(O)-Q^(2a), —NR^(3a)C(O)CH₂O-Q^(2a), or —C(O)NR^(3a)-Q^(2a) wherein R^(3a) is hydrogen atom or C₁₋₆ group;

ring Q^(2a) is 5- or 6-membered heteroaryl group;

W^(3a) is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆, alkoxy;

R¹² and R¹³ are independently

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₃₋₁₀ cycloalkyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (6) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (7) C₂₋₆ alkynyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (8) cyano group, or (9) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups;

when R¹³ and W^(3a) are attached to the adjacent carbon atoms on ring Q^(2a), they may be combined with the carbon atoms to form 5- or 6-membered cycloalkane ring; and

R¹⁴ is hydroxy group, or C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy.

[14] The compound according to [12] or [13] or a pharmaceutically acceptable salt thereof wherein ring Q^(1a) is phenyl group. [15] The compound according to any one of [12] to [14] or a pharmaceutically acceptable salt thereof wherein W^(2a)-Q^(2a) is —NHC(O)-Q^(2a). [16] The compound according to any one of [12] to [14] or a pharmaceutically acceptable salt thereof wherein W^(2a)-Q^(2a) is —C(O)NH-Q^(2a). [17] The compound according to any one of [12] to [16] or a pharmaceutically acceptable salt thereof wherein ring Q^(2a) is pyridyl group, pyrimidyl group, pyridazyl group, pyrazyl group, oxazolyl group, thiazolyl group, isoxazolyl group, or isothiazolyl group. [18] The compound according to any one of [12] to [16] or a pharmaceutically acceptable salt thereof wherein ring Q^(2a) is pyridyl group, pyridazyl group, pyrazyl group, oxazolyl group, thiazolyl group, or isoxazolyl group. [19] The compound according to any one of [12] to [16] or a pharmaceutically acceptable salt thereof wherein ring Q^(2a) is pyridyl group. [20] The compound according to any one of [12] to [19] or a pharmaceutically acceptable salt thereof wherein R¹² and R¹³ are independently (1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or (6) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups. [21] The compound according to any one of [12] to [20] or a pharmaceutically acceptable salt thereof wherein R¹² and R¹³ are independently (1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, or (4) amino group. [22] The compound according to any one of [12] to [21] or a pharmaceutically acceptable salt thereof wherein R¹³ is halogen atom, C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms, or amino group; and R¹² is hydrogen atom. [23] The compound according to any one of [12] to [22] or a pharmaceutically acceptable salt thereof wherein W^(3a) is methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms; and R¹⁴ is hydroxy group. [24] The compound according to any one of [1] to [23] or a pharmaceutically acceptable salt thereof wherein R¹ and R² are hydrogen atom. [25] The compound according to [1] which is represented by formula (1b):

or a pharmaceutically acceptable salt thereof, wherein X¹ is N or CR²⁶;

X² is N or CR²⁸;

provide that at least one of X¹ and X² is N;

R²¹, R²², R²³, R²⁴, and R²⁵ are independently

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms, or (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 halogen atoms;

W^(2b) is —NHC(O)— or —C(O)NH—;

R²⁶, R²⁷, R²⁸, and R²⁹ are independently

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or (6) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups. [26] The compound according to [25] or a pharmaceutically acceptable salt thereof wherein R²² is halogen atom or C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms. [27] The compound according to [25] or a pharmaceutically acceptable salt thereof wherein R²² is halogen atom or trifluoromethyl group. [28] The compound according to any one of [25] to [27] or a pharmaceutically acceptable salt thereof wherein R²¹, R²³, R²⁴, and R²⁵ are independently (1) hydrogen atom, (2) halogen atom, or (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms. [29] The compound according to any one of [25] to [28] or a pharmaceutically acceptable salt thereof wherein W^(2b) is —NHC(O)—. [30] The compound according to any one of [25] to [29] or a pharmaceutically acceptable salt thereof wherein X¹ is N. [31] The compound according to any one of [25] to [30] or a pharmaceutically acceptable salt thereof wherein X¹ is N; and X² is CH. [32] The compound according to any one of [25] to [31] or a pharmaceutically acceptable salt thereof wherein R²⁷ is halogen atom, C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms, or amino group; and R²⁹ is hydrogen atom. [33] The compound according to any one of [25] to [32] or a pharmaceutically acceptable salt thereof wherein R²⁷ is methyl group substituted with 1 to 3 fluorine atoms; and R²⁹ is hydrogen atom. [34] The compound according to any one of [25] to [33] or a pharmaceutically acceptable salt thereof wherein R²⁷ is methyl group substituted with 2 fluorine atoms; and R²⁹ is hydrogen atom. [35] The compound according to [1] which is represented by formula (1c):

or a pharmaceutically acceptable salt thereof, wherein R³² is halogen atom or C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms; and

R³³ and R³⁴ are independently hydrogen atom, or halogen atom.

[36] The compound according to [35] or a pharmaceutically acceptable salt thereof wherein R³² is fluorine atom, chlorine atom, or trifluoromethyl group. [37] The compound according to [1] selected from the following compounds or a pharmaceutically acceptable salt thereof:

6-(hydroxymethyl)-N-[l-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 10),

6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 12),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 17),

5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 18),

6-(hydroxymethyl)-5-(trifluoromethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 19),

6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 39),

6-(hydroxymethyl)-5-methyl-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 42),

5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 45),

5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 46),

N-[1-(3,4-difluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 54),

N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 55),

5-(difluoromethyl)-N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 57),

5-(difluoromethyl)-N-{1-[3-fluoro-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 60),

N-[1-(3-chloro-4-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 61),

N-[1-(3-bromo-4-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 62),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-methoxy-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 65),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[4-methyl-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 70),

N-[1-(3,4-dichlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 71),

N-[1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 75),

N-[l-(3-bromo-5-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 76),

N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 78),

N-[1-(3,5-difluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 79), and

6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]pyridazine-3-carboxamide (Example 85).

[38] The compound according to [1] selected from the following compounds or a pharmaceutically acceptable salt thereof:

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 17),

5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 18),

N-[1-(3,4-difluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 54),

N-[1-(3-chlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 55),

5-(difluoromethyl)-N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 57),

N-[1-(3-bromobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 58),

5-(difluoromethyl)-N-{1-[3-fluoro-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 60),

N-[1-(3-chloro-4-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 61),

N-[1-(3-bromo-4-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 62),

5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3-methylbenzyl)-1H-imidazol-4-yl]nicotinamide (Example 63),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-methoxy-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 65),

N-[1-(4-chloro-3-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 66),

N-[l-(4-bromo-3-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 67),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[4-methyl-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 70),

N-[l-(3,4-dichlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 71),

5-(difluoromethyl)-N-{1-[3-fluoro-4-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 74),

N-[1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 75),

N-[1-(3-bromo-5-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 76),

N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 78),

N-[1-(3,5-difluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 79), and

N-[1-(3-bromo-4-chlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 80).

[39] The compound according to [1] selected from the following compounds or a pharmaceutically acceptable salt thereof:

6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 12),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 17),

5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 18),

6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 39),

5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 45),

5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide (Example 46),

5-(difluoromethyl)-N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 57),

5-(difluoromethyl)-N-{1-[3-fluoro-5-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-6-(hydroxymethyl)nicotinamide (Example 60),

N-[1-(3-chloro-4-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 61),

N-[1-(3-bromo-4-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 62),

5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[4-methyl-3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide (Example 70),

N-[1-(3,4-dichlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 71),

N-[1-(3,5-dichlorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 75),

N-[1-(3-bromo-5-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 76),

N-[1-(3-chloro-5-fluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 78), and

N-[1-(3,5-difluorobenzyl)-1H-imidazol-4-yl]-5-(difluoromethyl)-6-(hydroxymethyl)nicotinamide (Example 79).

[40] A medicament comprising the compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof as an active ingredient. [41] An anti-tumor agent comprising the compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof as an active ingredient. [42] The anti-tumor agent according to [41] wherein the tumor is acute leukemia, chronic lymphatic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small-cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder or bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, chorioepithelioma, endometrial cancer, cervical cancer, urothelial cancer, renal cell cancer, prostate cancer, testicular tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, or soft tissue sarcoma. [43] A medicament comprising the compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof in combination with another anti-cancer agent selected from the group consisting of an anti-cancerous alkylating agent, an anti-cancerous antimetabolite, an anti-cancerous antibiotic, a plant-based anti-cancer agent, an anti-cancerous platinum coordination compound, an anti-cancerous camptothecin derivative, an anti-cancerous tyrosine kinase inhibitor, a serine-threonine kinase inhibitor, a phospholipid kinase inhibitor, a monoclonal antibody, an interferon, a biological response modifier, a hormone preparation, an immune checkpoint inhibitor, an epigenetics-related molecule inhibitor, a post-translational protein modification inhibitor, and other anti-cancer agent or a pharmaceutically acceptable salt thereof. [44] A method for treating cancer which comprises administering a therapeutically effective amount of the compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof to a patient in need thereof. [45] Use of the compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating cancer. [46] A pharmaceutical composition for use in the treatment of cancer, comprising the compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof. [47] The compound according to any one of [1] to [39] or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

Effects of the Invention

The present compound has a potent inhibitory effect on the sphere-forming ability of cancer cells. In addition, the preferred present compound has high bioavailability after oral administration. Thus, the present compound is useful as an orally-available anti-tumor agent.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention is explained in detail. The number of carbon atoms in the definition of the “substituent” used herein may be expressed as, for example, “C₁₋₆”. Specifically, the term “C₁₋₆ alkyl” is used for the same meaning as alkyl group having 1 to 6 carbon atoms.

Specific examples of “halogen atom” used herein include fluorine atom, chlorine atom, bromine atom, and iodine atom.

The term “C₁₋₆ alkyl group” used herein means a straight or branched, saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred examples thereof include “C₁₋₄ alkyl group”. Specific examples of the “C₁₋₆ alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, l-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

The term “C₂₋₆ alkenyl group” used herein means a straight or branched, unsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3 carbon-carbon double bonds. Preferred examples thereof include “C₂₋₄ alkenyl group”. Specific examples of the “C₂₋₆ alkenyl group” include ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “C₂₋₆ alkynyl group” used herein means a straight or branched, unsaturated hydrocarbon group having 2 to 6 carbon atoms and 1 to 3 carbon-carbon triple bonds. Preferred examples thereof include “C₂₋₄ alkynyl group”. Specific examples of the “C₂₋₆ alkynyl group” include ethynyl, propynyl, butynyl, penthynyl, and hexynyl.

The term “C₁₋₄ alkylene group” used herein means a straight or branched, divalent saturated hydrocarbon group having 1 to 4 carbon atoms, or a divalent saturated hydrocarbon group containing a cyclic structure having 3 to 4 carbon atoms.

Specific examples of the straight or branched “C₁₋₄ alkylene group” include methylene, ethylene, trimethylene, tetramethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene, 2-methylethylene, and 1-ethylethylene. Preferred examples thereof include methylene and ethylene.

Specific examples of the “C₁₋₄ alkylene group” containing a cyclic structure include the following groups:

The term “C₃₋₄ alkenylene group” used herein means a straight or branched, divalent hydrocarbon group having 3 to 4 carbon atoms and a carbon-carbon double bond. Specific examples of the “C₃₋₄ alkenylene group” include propenylene and butenylene.

The term “C₃₋₄ alkynylene group” used herein means a straight or branched, divalent hydrocarbon group having 3 to 4 carbon atoms and a carbon-carbon triple bond. Specific examples of the “C₃₋₄ alkynylene group” include propynylene and butynylene.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkoxy group” used herein is as defined in the above “C₁₋₆ alkyl”. Preferred examples thereof include “C₁₋₄ alkoxy group”. Specific examples of the “C₁₋₆ alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term “C₃₋₁₀ cycloalkyl group” used herein means a 3- to 10-membered monocyclic or polycyclic, saturated or partially-unsaturated hydrocarbon group. The group is preferably “C₃₋₇ cycloalkyl group”, and more preferably cyclohexyl group. Specific examples of the “C₃₋₁₀ cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, decalinyl, adamantyl, and norbornyl.

The term “C₆₋₁₀ aryl group” used herein means an aromatic hydrocarbon group having 6 to 10 carbon atoms. The group is preferably “C₆ aryl group” (phenyl). Specific examples of the “C₆₋₁₀ aryl group” include phenyl, 1-naphthyl, or 2-naphthyl.

Examples of the term “5- to 10-membered heteroaryl group” used herein include a 5- to 10-membered mono- or bicyclic aromatic group which contains the same or different one or more (e.g. 1 to 4) heteroatoms selected from the group consisting of nitrogen atom, sulfur atom, and oxygen atom. The bicyclic heteroaryl group also encompasses a fused ring group of a monocyclic heteroaryl group mentioned above with an aromatic group (such as benzene and pyridine) or a non-aromatic ring (such as cyclohexyl and piperidine). Specific examples of the “heteroaryl group” include the groups of the following formulae:

The bond across a ring in the above formulae means that a “group” is linked at any replaceable position in the ring. For example, when a group is the heteroaryl group of the following formula:

the group means 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group.

Furthermore, when a “heteroaryl group” is a bicyclic group, for example, the group of the following formula:

the group may be 1-benzimidazolyl, 2-benzimidazolyl, or 4-, 5-, 6- or 7-benzimidazolyl.

The term “aminocarbonyl group” used herein means a formyl group wherein hydrogen atom therein is replaced with amino group.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆alkyl-carbonylamino group” used herein is as defined in the above “C₁₋₆ alkyl”. The group is preferably “C₁₋₄ alkyl-carbonylamino group”, and more preferably methylcarbonylamino group (acetamido group).

The “C₆₋₁₀ aryl” moiety of the term “C₆₋₁₀ aryloxy group” is as defined in the above “C₆₋₁₀ aryl”. Preferred examples thereof include “C₆ aryloxy group” (phenoxy group) The “C₁₋₆ alkoxy” moiety of the term “C₁₋₆ alkoxy-carbonyl group” used herein is as defined in the above “C₁₋₆ alkoxy”. Preferred examples thereof include “C₁₋₄ alkoxy-carbonyl group”. Specific examples of the “C₁₋₆ alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkyl-carbonyl group” used herein is as defined in the above “C₁₋₆ alkyl”. Preferred examples thereof include “C₁₋₄ alkyl-carbonyl group”. Specific examples of the “C₁₋₆ alkyl-carbonyl group” include acetyl, ethylcarbonyl, and propylcarbonyl. The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkylsulfonyl group” used herein is as defined in the above “C₁₋₆ alkyl”. Preferred examples thereof include “C₁₋₄ alkylsulfonyl group”. Specific examples of the “C₁₋₆ alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

The “C₁₋₆ alkyl” moiety of the term “C₁₋₆ alkylsulfonylamino group” used herein is as defined in the above “C₁₋₆ alkyl”. Preferred examples thereof include “C₁₋₄ alkylsulfonylamino group”. Specific examples of the “C₁₋₆ alkylsulfonylamino group” include methylsulfonylamino, ethylsulfonylamino, and propylsulfonylamino.

The “C₁₋₆ alkoxy” moiety of the term “C₁₋₆alkoxy-carbonylamino group” used herein is as defined in the above “C₁₋₆ alkoxy”. Preferred examples thereof include “C₁₋₄ alkoxy-carbonylamino group”. Specific examples of the “C₁₋₆ alkoxy-carbonylamino group” include methoxycarbonylamino, ethoxycarbonylamino, and propoxycarbonylamino.

The term “C₁₋₆ alkyl-carbonyloxy group” used herein means an oxy group substituted with the above “C₁₋₆ alkyl-carbonyl group”. Preferred examples thereof include “C₁₋₄ alkyl-carbonyloxy group”. Specific examples of the “C₁₋₆ alkyl-carbonyloxy group” include acetoxy, propionyloxy, and butyryloxy.

The term “aminosulfonyl group” used herein means a sulfo group wherein hydroxy group therein is substituted with amino group.

Examples of the substituent in the terms “optionally-substituted C₁₋₆ alkyl group”, “optionally-substituted C₂₋₆ alkenyl group”, “optionally-substituted C₂₋₆ alkynyl group”, “optionally-substituted C₁₋₄ alkylene group”, “optionally-substituted C₃₋₄ alkenylene group”, “optionally-substituted C₃₋₄ alkynylene group”, “optionally-substituted C₁₋₆ alkoxy group”, “optionally-substituted C₁₋₆ alkyl-carbonyl group”, “optionally-substituted C₁₋₆ alkylsulfonyl group”, “optionally-substituted C₁₋₆ alkoxy-carbonyl group”, “optionally-substituted C₁₋₆ alkyl-carbonylamino group”, “optionally-substituted C₁₋₆ alkylsulfonylamino group”, “optionally-substituted C₁₋₆ alkoxy-carbonylamino group”, “optionally-substituted C₁₋₆ alkyl-carbonyloxy group” include hydroxy group, halogen atom, C₃₋₇ cycloalkyl group, and C₁₋₆ alkoxy group, and preferably fluorine atom.

Examples of the substituent in the terms “optionally-substituted C₆₋₁₀ aryl group”, “optionally-substituted C₃₋₁₀ cycloalkyl group”, “optionally-substituted 5- to 10-membered heteroaryl group”, “optionally-substituted 5- or 6-membered cyclic amino group”, and “optionally-substituted 5- or 6-membered cyclic aminocarbonyl group” include

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) C₆₋₁₀ aryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, and

(f) 5- or 6-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(g) C₆₋₁₀ aryloxy which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(h) hydroxy,

(i) amino which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(j) aminocarbonyl wherein the amino moiety thereof may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(k) C₁₋₆ alkoxy-carbonyl wherein the alkoxy moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(l) C₁₋₆ alkyl-carbonyl wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(m) C₁₋₆ alkylsulfonyl wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(n) C₁₋₆ alkyl-carbonylamino wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(o) C₁₋₆ alkylsulfonylamino wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(p) C₁₋₆ alkoxy-carbonylamino wherein the alkoxy moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(q) C₁₋₆ alkyl-carbonyloxy wherein the alkyl moiety thereof may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(r) aminosulfonyl wherein the amino moiety thereof may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups, and

(s) C₃₋₁₀ cycloalkyl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy.

Examples of the substituent in the terms “optionally-substituted amino group”, “optionally-substituted aminocarbonyl group”, and “optionally-substituted aminosulfonyl group” include C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, and preferably C₁₋₃ alkyl.

In the present compound of formula (1′), W¹, W², W³, R¹, R², R⁴, R⁵, n, ring Q¹, and ring Q² are preferably those shown below, but the technical scope of the present invention should not be limited to the following compounds.

W¹ preferably includes C₁₋₄ alkylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy. W¹ is more preferably methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 halogen atoms; and furthermore preferably methylene group.

W²-Q² preferably includes —NR^(3a)C(O)-Q², —NR^(3a)C(O)CH₂O-Q², or —C(O)NR^(3a)-Q² wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl group. W²-Q² is more preferably —NHC(O)-Q² or —C(O)NH-Q²; and furthermore preferably —NHC(O)-Q².

In another embodiment, W²-Q² preferably includes —NR^(3a)C(O)-Q², —NR^(3a)C(O)CH₂O-Q², —C(O)NR^(3a)-Q², or —NR^(3a)C(O)—CH═CH-Q² wherein R^(3a) is hydrogen atom or C₁₋₆ alkyl group. W²-Q² is more preferably —NHC(O)-Q², —C(O)NH-Q², or —NHC(O)—CH═CH-Q²; and furthermore preferably —NHC(O)-Q².

Preferably, R¹ and R² independently include hydrogen atom, halogen atom, and C₁₋₄ alkyl group which may be optionally substituted with the same or different 1 to 3 halogen atoms. R¹ and R² are more preferably hydrogen atom, chlorine atom, or methyl group; and furthermore preferably hydrogen atom.

Ring Q¹ preferably includes

(1) C₆₋₁₀ aryl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) phenyl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(f) 5- or 6-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(g) phenoxy which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy,

(h) hydroxy,

(i) amino which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups, and

(j) aminocarbonyl wherein the amino moiety thereof may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups,

(2) C₃₋₁₀ cycloalkyl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of (a) to (j) defined in the above (1), or (3) 5- to 10-membered heteroaryl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of (a) to (j) defined in the above (1).

Ring Q¹ preferably includes

(1) phenyl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from the group consisting of

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy,

(d) cyano,

(e) phenyl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, and

(f) 5- or 6-membered heteroaryl which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, C₁₋₆ alkyl, and C₁₋₆ alkoxy, or

(2) pyridyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of (a) to (f) defined in the above (1).

Ring Q¹ furthermore preferably includes phenyl group which may be optionally substituted with the same or different 1 to 5 groups independently selected from

(a) halogen atom,

(b) C₁₋₆ alkyl which may be optionally substituted with the same or different 1 to 3 halogen atoms, and

(c) C₁₋₆ alkoxy which may be optionally substituted with the same or different 1 to 3 halogen atoms.

Ring Q¹ is furthermore preferably phenyl group substituted with the same or different 1 to 3 halogen atoms.

Ring Q² is preferably pyridyl group, pyrimidyl group, pyridazyl group, pyrazyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, or quinoxalinyl group. The ring is more preferably pyridyl group, pyridazyl group, pyrazyl group, oxazolyl group, thiazolyl group, isoxazolyl group, or quinolinyl group; furthermore preferably pyridyl group or pyrazyl group; and most preferably pyridyl group.

R⁴ preferably includes

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₃₋₁₀ cycloalkyl group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (6) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (7) C₂₋₆ alkynyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, (8) cyano group, or (9) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups.

R⁴ preferably includes

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (4) C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (5) C₂₋₆ alkenyl group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or (6) amino group which may be optionally substituted with the same or different 1 to 2 C₁₋₆ alkyl groups.

R⁴ furthermore preferably includes

(1) hydrogen atom, (2) halogen atom, (3) C₁₋₆ alkyl group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, or (4) amino group.

R⁴ is furthermore preferably methyl group substituted with 1 to 3 fluorine atoms; and most preferably methyl group substituted with 2 fluorine atoms.

W³ is preferably

(1) C₁₋₄ alkylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy, (2) C₃₋₄ alkenylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or (3) C₃₋₄ alkynylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms.

W³ is more preferably methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms, or ethylene group which may be optionally substituted with the same or different 1 to 4 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy; and furthermore preferably methylene group which may be optionally substituted with the same or different 1 to 2 halogen atoms.

Also, the preferred embodiment includes the present compound wherein one or more of ¹H in W³ are replaced with ²H(D) (i.e. deuterated form).

R⁵ preferably includes hydroxy group, or C₁₋₆ alkoxy group which may be optionally substituted with the same or different 1 to 3 groups independently selected from the group consisting of halogen atom, hydroxy, and C₁₋₆ alkoxy. R⁵ is more preferably hydroxy group.

n in the above [1] and m in the above [12] are independently selected from 1, 2, 3, 4, or 5. Preferably, n and m are independently 1, 2, or 3. When the number of the replaceable positions on the ring having the substituent R⁴ or R¹¹ is less than 5, n and m are independently selected from the maximum replaceable number of R⁴ or R¹¹. For example, when ring Q¹ is pyridyl group, m is selected from 1, 2, 3, or 4.

The present compound may be in the forms of a hydrate and/or a solvate. Thus, the present compound also encompasses hydrate and/or solvate such as ethanol solvate. Furthermore, the present compound encompasses all types of crystal forms of the present compound.

Specific examples of the pharmaceutically acceptable salt of the compound of formula (1′) include an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and an organic acid salt such as acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate.

The compound of formula (1′) may be in the form of a tautomer. Thus, the present compound also encompasses the tautomer of the compound of formula (1′).

The compound of formula (1′) may contain one or more asymmetric carbon atoms. Thus, the present compound encompasses not only racemic forms of the compound of formula (1′) but also optically-active forms thereof. When the compound of formula (1′) contains two or more asymmetric carbon atoms, the compound can result in various stereoisomerisms. Thus, the present compound also encompasses the stereoisomer of the compound and a mixture or isolate thereof.

Also, the compound of formula (1′) encompasses the compound wherein one or more of ¹H are replaced with ²H(D) (i.e. deuterated form).

Preparations

The present compounds can be prepared according to processes shown below and according to the processes in combination with known compounds and known synthesis processes.

As appropriate, each compound used as a starting compound may be used in the salt form. The shown processes are just examples to prepare the compounds, and may be optionally modified by those skilled in the organic synthesis field.

In each process shown below, any functional groups which need to be protected may be optionally protected and then deprotected after the reaction or reactions are completed to give the desired compound even though the use of protective groups is not specifically described.

The protective group used herein includes any conventional groups described in various literatures, for example, T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999). In more detail, specific examples of the protective groups for amino group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl, and specific examples of the protective groups for hydroxy group include trialkylsilyl, acetyl, and benzyl.

The protective groups can be introduced and cleaved according to commonly-used methods in synthetic organic chemistry (e.g. the method described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999)) and similar methods thereto.

Preparation 1

One of the compounds of formula (1′), the compound of formula (1-7) is prepared by linking each fragment in positions a and b, respectively:

wherein W¹, W³, R¹, R², R⁴, R⁵, n, ring Q¹, and ring Q² are as defined in the above [1].

The processes for forming each bond in positions a and b can be illustrated as follows, but the order of procedure for forming each bond may be optionally changed:

wherein W¹, W³, R¹, R², R⁴, R⁵, n, ring Q¹, and ring Q² are as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; L is a leaving group (such as iodine atom, bromine atom, chlorine atom, and substituted sulfonyl group (e.g. methanesulfonyl group and p-toluenesulfonyl group)).

Compound (1-1) may be a commercially available product or be prepared according to known synthesis processes (e.g. New Version of Heterocyclic Compound (advanced level) edited by Kodansha Scientific Ltd.).

Step 1-1: Preparation Process of Compound (1-2)

Compound (1-2) is prepared by hydrolyzing compound (1-1) according to a similar process to a known process (e.g. Protective Groups in Organic Synthesis 3^(rd) Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by R. C. Larock, VCH publisher Inc., 1989).

Step 1-2: Preparation Process of Compound (1-5)

Compound (1-5) is prepared by the alkylation reaction of compounds (1-3) and (1-4) in an inert solvent in the presence of a base.

Specific examples of the base include an organic base such as triethylamine, diisopropylethylamine, and pyridine; an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and a metal alkoxide such as sodium methoxide and potassium tert-butoxide.

Specific examples of the inert solvent include a halogenated hydrocarbon such as chloroform and dichloromethane; an aromatic hydrocarbon such as toluene; an ether-type solvent such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; an aprotic polar solvent such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethylsulfoxide; a basic solvent such as pyridine; and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 20° C. to 100° C., but is not limited thereto. The reaction time is typically 30 minutes to 48 hours, preferably 30 minutes to 10 hours.

Step 1-3: Preparation Process of Compound (1-6)

Compound (1-6) is prepared by reducing the nitro group in compound (1-5). For example, reductions under an acidic condition with a metal such as zinc, iron, and tin or a metal salt such as tin (II) chloride; reductions with a sulfide such as sodium hypodisulfite (Na₂S₂O₄); and catalytic hydrogenations with a metal catalyst such as palladium/carbon, Raney nickel, platinum oxide/carbon, and rhodium/carbon under hydrogen atmosphere may be used.

In the reduction with a metal or a metal salt, the amount of the metal or metal salt to be used is typically about 1 mole to 100 moles, preferably about 10 moles to 30 moles per mole of compound (1-5). Also, the amount of the acid to be used is typically about 1 mole to 100 moles, preferably about 10 moles to 30 moles per mole of compound (1-5). The reduction is typically carried out in a solvent which has no negative effect on the reaction (e.g. ethanol). The reaction temperature is typically 0° C. to 100° C., but is not limited thereto. The reaction time is typically 30 minutes to 8 hours.

In the catalytic hydrogenation reaction, the amount of the metal catalyst to be used for compound (1-5) is typically 0.1% by weight to 1000% by weight, preferably 1% by weight to 100% by weight. The reaction may be carried out in a solvent such as an alcohol such as methanol; an ether such as tetrahydrofuran; and an ester such as ethyl acetate. The hydrogen pressure is typically 1 atm to 100 atms, preferably 1 atm to 5 atms. The reaction temperature is typically 0° C. to 120° C., preferably 20° C. to 80° C., but is not limited thereto. The reaction time is typically 30 minutes to 72 hours, preferably 1 hour to 48 hours.

Also, the reaction may be carried out in the presence of an acid catalyst, as appropriate. For example, an organic acid such as formic acid, acetic acid, and trifluoroacetic acid, and an inorganic acid such as sulfuric acid, hydrochloric acid, and hydrobromic acid are used as the acid catalyst. The amount of the acid to be used is 0.1 mole or more per mole of compound (1-5).

Step 1-4: Preparation Process of Compound (1-7)

Compound (1-7) is prepared by reacting compound (1-2) with compound (1-6) in an inert solvent in the presence of a condensation agent.

The reaction may be carried out in the presence of a base, as appropriate. The reaction temperature is typically about −20° C. to the boiling point of the used solvent, but is not limited thereto. The reaction time is typically 10 minutes to 48 hours, which may vary according to various conditions such as a reaction temperature, a condensation agent, a starting material, and a solvent to be used.

Specific examples of the condensation agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA), N,N-carbonyldiimidazole (CDI), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), and diphenyl chlorophosphate. As appropriate, the reaction may be carried out with the addition of an additive such as N-hydroxysuccinimide (HOSu), l-hydroxybenzotriazole (HOBt), and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt).

Specific examples of the base include an organic base such as triethylamine, diisopropylethylamine, and pyridine; an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and a metal alkoxide such as sodium methoxide and potassium tert-butoxide.

Specific example of the inert solvent include a halogenated hydrocarbon such as chloroform and dichloromethane; an aromatic hydrocarbon such as toluene; an ether-type solvent such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; an aprotic polar solvent such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethylsulfoxide; a basic solvent such as pyridine; and a mixture thereof.

Compound (1-7) is also prepared by reacting an acid halide or an acid anhydride derived from compound (1-2) with compound (1-6) in an inert solvent in the presence of a base.

Preparation 2

In the compounds of formula (1-1), the compounds of formulae (2-5), (2-8), (2-11), and (2-13) are prepared according to, for example, the following process.

wherein R⁴, n, and ring Q² are as defined in the above [1]; A is boronic acid or boronate; R¹⁰¹ is C₁₋₆ alkyl group; R¹⁰² is optionally-substituted C₁₋₆ alkyl group; R^(a) and R^(b) are independently the same or different hydrogen atom or methyl group; R is benzenesulfonyl group substituted with one or two nitro groups; X is halogen atom, and L is a leaving group (such as iodine atom, bromine atom, chlorine atom, and substituted sulfonyl group (e.g. methanesulfonyl group and p-toluenesulfonyl group)).

Step 2-1: Preparation Process of Compound (2-3)

Compound (2-3) is prepared by reacting compound (2-1) with compound (2-2) in an inert solvent in the presence of a palladium catalyst and a base.

Specific examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium (0), bis(dibenzylideneacetone)palladium (0), tris(dibenzylideneacetone)dipalladium (0), bis(tri-tert-butylphosphine)palladium (0), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride.

Specific examples of the base include an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.

Specific examples of the inert solvent include toluene, 1,2-dimethoxyethane, 1,4-dioxane, DMF, water, and a mixture thereof.

The reaction temperature is typically 50° C. to 150° C., preferably 80° C. to 120° C., but is not limited thereto. Also, the reaction may be carried out under microwave irradiation. The reaction time is typically 1 hour to 24 hours, preferably 2 hours to 12 hours.

Step 2-2: Preparation Process of Compound (2-4)

Compound (2-4) is prepared by reacting compound (2-3) with osmium tetroxide or potassium osmate (IV) dihydrate in the presence of sodium periodate.

Examples of the solvent used include acetone, 1,4-dioxane, THF, tert-butanol, water, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 25° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 1 hour to 24 hours.

Also, compound (2-4) is prepared by treating compound (2-3) with oxygen currents including ozone and then reacting the treated compound with a reducing agent such as dimethyl sulfide in a solvent such as dichloromethane, ethyl acetate, and methanol. The reaction temperature is typically −78° C. to room temperature, but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 6 hours to 24 hours.

Step 2-3: Preparation Process of Compound (2-5)

Compound (2-5) is prepared by reacting compound (2-4) with an organometallic reagent or a hydride reducing agent.

Specific examples of the organometallic reagent include methyllithium reagent and methyl Grignard reagent.

Specific examples of the hydride reducing agent include sodium borohydride and sodium cyanoborohydride.

The solvent used in the reaction with the organometallic reagent includes THF, diethyl ether, and a mixture thereof, and the solvent used in the reaction with the hydride reducing agent includes methanol, ethanol, dichloromethane, toluene, and a mixture thereof.

The reaction temperature is typically −78° C. to 50° C., preferably 0° C. to 25° C., but is not limited thereto. The reaction time is typically 5 minutes to 12 hours, preferably 30 minutes to 6 hours.

Step 2-4: Preparation Process of Compound (2-6)

Compound (2-6) wherein L is substituted sulfonyl group is prepared by reacting compound (2-5) with an alkyl- or aryl-sulfonyl chloride in an inert solvent in the presence of a base.

Specific examples of the alkyl- or aryl-sulfonyl chloride include methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and 2,4,6-trimethylbenzene chloride.

Examples of the base include an organic base such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate.

Examples of the inert solvent include THF, dichloromethane, toluene, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 1 hour to 24 hours.

Compound (2-6) wherein L is halogen is prepared by reacting compound (2-5) with a halogenating agent or alkyl- or aryl-sulfonyl chloride and an alkali metal halide in an inert solvent.

Examples of the halogenating agent include thionyl chloride, oxalyl dichloride, phosphorus tribromide, phosphorus pentabromide, and phosphorus oxychloride.

Specific examples of the alkyl- or aryl-sulfonyl chloride include methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and 2,4,6-trimethylbenzenesulfonyl chloride, and examples of the alkali metal halide include lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, and potassium iodide.

Step 2-5: Preparation Process of Compound (2-8)

Compound (2-8) is prepared by reacting compound (2-6) with sodium alkoxide of formula (2-7). As appropriate, sodium alkoxide may be prepared from sodium metal and various alcohols.

Examples of the solvent used include methanol, ethanol, THF, DMF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 6 hours.

Step 2-6: Preparation Process of Compound (2-10)

Compound (2-10) is prepared by the Mitsunobu reaction of compound (2-5) and benzenesulfonamide of formula (2-9) in an inert solvent in the presence of a Mitsunobu reagent.

Examples of the Mitsunobu reagent include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), triphenylphosphine, and tributylphosphine. Also, cyanomethylenetrimethylphosphorane (Tsunoda Reagent) may be used.

Examples of the inert solvent include toluene, benzene, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 48 hours, preferably 12 hours to 24 hours.

Step 2-7: Preparation Process of Compound (2-11)

Compound (2-11) is prepared by reacting compound (2-10) with a thiol in the presence of a base and cleaving benzenesulfonyl group.

Examples of the thiol include thiophenol and dodecanethiol.

Examples of the base include an inorganic base such as cesium carbonate and potassium carbonate.

The solvent used includes DMF, toluene, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 48 hours, preferably 3 hours to 12 hours.

Step 2-8: Preparation Process of Compound (2-12)

Compound (2-12) is prepared by reacting compound (2-6) with di-tert-butyl iminodicarboxylate in an inert solvent in the presence of a base.

Examples of the base include sodium hydride, potassium tert-butoxide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium diisopropylamide.

Examples of the inert solvent include DMF, THF, and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 25° C. to 120° C., but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 6 hours to 24 hours.

Step 2-9: Preparation Process of Compound (2-13)

Compound (2-13) is prepared by cleaving Boc group in compound (2-12) under an acidic condition and then treating the resulting amine with an acylating agent in an inert solvent in the presence of a base.

Examples of the acid used in the deprotection step include trifluoroacetic acid, hydrochloric acid, and sulfuric acid.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 6 hours to 24 hours.

The acylating agent includes carboxylic halide such as R¹⁰²COCl and R¹⁰²COBr; and carboxylic anhydride such as (R¹⁰²CO)₂O. As appropriate, a promoter such as DMAP may be used.

Examples of the base include an organic base such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate.

Examples of the inert solvent include dichloromethane, 1,2-dichloroethane, THF, toluene, ethyl acetate, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 6 hours.

Preparation 3

One of the compounds of formula (2-1), the compound of formula (3-5) is prepared according to, for example, the following process.

wherein ring Q² is as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; X is halogen atom; and Y is bromine atom or iodine atom.

Step 3-1: Preparation Process of Compound (3-2)

Compound (3-2) is prepared by reacting compound (3-1) with a brominating agent in an inert solvent in the presence of a radical initiator.

Specific examples of the radical initiator include azobisisobutyronitrile (AIBN) and benzoyl peroxide (BPO).

Specific examples of the brominating agent include N-bromosuccinimide and bromine.

Examples of the inert solvent include carbon tetrachloride, chlorobenzene, and a mixture thereof.

The reaction temperature is typically 50° C. to 150° C., preferably 80° C. to 120° C., but is not limited thereto. The reaction time is typically 3 hours to 48 hours, preferably 4 hours to 12 hours.

Step 3-2: Preparation Process of Compound (3-4)

Compound (3-4) is prepared by reacting compound (3-2) with silver nitrate in an inert solvent.

Specific examples of the inert solvent include acetonitrile, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 50° C. to 150° C., preferably 80° C. to 120° C., but is not limited thereto. The reaction time is typically 3 hours to 48 hours, preferably 4 hours to 12 hours.

Step 3-3: Preparation Process of Compound (3-4)

Compound (3-4) is also prepared by reacting compound (3-3) with an organometallic reagent and then treating the resulting compound with a formylating agent.

Examples of the organometallic reagent include isopropylmagnesium chloride-lithium chloride complex, isopropylmagnesium chloride, and n-butyllithium.

Examples of the solvent used include THF, diethyl ether, toluene, and a mixture thereof.

Examples of the formylating agent include DMF and N-formylmorpholine.

The reaction temperature is typically −78° C. to 50° C., preferably −30° C. to 25° C., but is not limited thereto. The reaction time is typically 30 minutes to 24 hours, preferably 1 hour to 6 hours.

Step 3-4: Preparation Process of Compound (3-5)

Compound (3-5) is prepared by reacting compound (3-4) with a deoxofluorinating agent in an inert solvent.

Specific examples of the deoxofluorinating agent include diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®), XtalFluor-E®, XtalFluor-M®, and 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead®). As appropriate, compounds such as DBU, triethylamine trihydrofluoride, and triethylamine dihydrofluoride may be used as a promoter.

Specific examples of the inert solvent include dichloromethane, 1,2-dichloroethane, toluene, THF, and a mixture thereof.

The reaction temperature is typically −20° C. to 50° C., preferably 0° C. to 25° C., but is not limited thereto. The reaction time is typically 10 minutes to 12 hours, preferably 30 minutes to 3 hours.

Compound (3-5) is also prepared by reacting compound (3-4) with sulfur tetrafluoride.

Preparation 4

One of the compounds of formula (1-1), the compound of formula (4-3) is prepared according to, for example, the following process.

wherein R⁴, n, and ring Q² are as defined in the above [1]; and R¹⁰¹ is C₁₋₆ alkyl group.

Step 4-1: Preparation Process of Compound (4-2)

Compound (4-2) is prepared by hydrobrominating compound (4-1) with a brominating agent in an inert solvent and then treating the resulting compound with a base.

Examples of the brominating agent used in the hydrobromination step include N-bromosuccinimide.

Examples of the inert solvent include tert-butanol, water, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 6 hours.

Examples of the base used in the treatment step include sodium hydride, potassium hydride, NaHMDS, potassium-tert-butoxide, sodium hydroxide, potassium hydroxide, and triethylamine.

Examples of the inert solvent include THF, 1,4-dioxane, DMF, and a mixture thereof.

The reaction temperature is typically 0° C. to 80° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 30 minutes to 8 hours, preferably 1 hour to 4 hours.

Step 4-2: Preparation Process of Compound (4-3)

Compound (4-3) is prepared by hydrogenating compound (4-2) with a palladium catalyst in an inert solvent.

Examples of the palladium catalyst include palladium-carbon and palladium hydroxide.

Examples of the solvent used include THF, methanol, ethanol, 2-propanol, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 25° C. to 80° C., but is not limited thereto. The reaction time is typically 1 hour to 12 hours, preferably 2 hours to 6 hours.

Preparation 5

One of the compounds of formula (1-1), the compound of formula (5-1) is prepared according to, for example, the following process.

wherein R⁴, n, and ring Q² are as defined in the above [1]; and R¹⁰1 is C₁₋₆ alkyl group.

Compound (5-1) is prepared by reacting compound (4-1) with osmium tetroxide in an appropriate solvent in the presence of N-methylmorpholine-N-oxide.

Examples of the solvent used include acetone, 1,4-dioxane, THF, tert-butanol, water, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 25° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 6 hours to 24 hours.

Preparation 6

One of the compounds of formula (1-1), the compound of formula (6-2) is prepared according to, for example, the following process.

wherein R⁴, n, and ring Q² are as defined in the above [1]; and R¹⁰¹ is C₁₋₆ alkyl group.

Compound (6-2) is prepared by reacting compound (6-1) with paraformaldehyde under microwave irradiation with heating in the presence of a base.

Examples of the base include N,N-diisopropylethylamine, triethylamine, pyridine, and DBU.

Examples of the solvent used include water, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 100° C. to 200° C., preferably 120° C. to 180° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 6 hours.

Preparation 7

One of the compounds of formula (1-1), the compound of formula (7-2) is prepared according to, for example, the following process.

wherein R⁴, n, and ring Q² are as defined in the above [1]; and R¹⁰¹ is C₁₋₆ alkyl group.

Compound (7-2) is prepared by reacting compound (7-1) with a carboxylic acid chloride in the presence of a base to convert the compound to an acid anhydride, and then reducing the resulting acid anhydride with a hydride reducing agent.

Examples of the base used in the step for producing the acid anhydride include N-methylmorpholine, N,N-diisopropylethylamine, triethylamine, pyridine, and DBU.

Specific examples of the carboxylic acid chloride include isobutyl chloroformate, ethyl chloroformate, methyl chloroformate, and acetyl chloride.

Examples of the solvent used include DME, THF, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 25° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 6 hours.

Specific examples of the hydride reducing agent used in the reduction step include sodium borohydride and sodium triacetoxyborohydride.

Examples of the solvent used include methanol, ethanol, 2-propanol, and THF.

The reaction temperature is typically 0° C. to 50° C., preferably 0° C. to 25° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 6 hours.

Preparation 8

One of the compounds of formula (1′), the compound of formula (8-3) is prepared according to, for example, the following process.

wherein W¹, R¹, R², R⁴, n, ring Q¹, and ring Q² are as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; and R^(c) and R^(d) are independently the same or different hydrogen atom, deuterium atom, or methyl group.

Step 8-1: Preparation Process of Compound (8-2)

Compound (8-2) is prepared from compounds (8-1) and (1-6) according to the process of Step 1-4.

Step 8-2: Preparation Process of Compound (8-3)

Compound (8-3) is prepared by reacting compound (8-2) with an organometallic reagent or a hydride reducing agent in an inert solvent.

Specific examples of the organometallic reagent include methyllithium reagent and methyl Grignard reagent. Examples of the solvent used include THF, diethyl ether, and a mixture thereof.

Specific examples of the hydride reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride, lithium triethylborohydride, diisobutylaluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, lithium borodeuteride, and lithium aluminum deuteride. Examples of the solvent used include methanol, ethanol, dichloromethane, toluene, and a mixture thereof.

The reaction temperature is typically −78° C. to 25° C., preferably 0° C. to 25° C., but is not limited thereto. The reaction time is typically 5 minutes to 12 hours, preferably 30 minutes to 6 hours.

Preparation 9

In the compounds of formula (1′), the compounds of formulae (9-2), (9-3), and (9-4) are prepared according to, for example, the following process.

wherein W¹, R¹, R², ring Q¹, and ring Q² are as defined in the above [1]; X is halogen atom; and R^(c) and R^(d) are independently the same or different hydrogen atom, deuterium atom, or methyl group.

Step 9-1: Preparation Process of Compound (9-2)

Compound (9-2) is prepared by the palladium-catalyzed cross-coupling reaction of compound (9-1) with various coupling reagents in an inert solvent.

Specific examples of the coupling reagent include methylchlorozinc, methylbromozinc, methyliodozinc, methylboronic acid, methylboronic acid pinacol ester, and methyltrifluoroborane-potassium salt.

Examples of the inert solvent include THF, toluene, 1,2-dimethoxyethane, 1,4-dioxane, DMF, and a mixture thereof. Specific examples of the palladium reagent include tetrakis(triphenylphosphine)palladium (0), bis(dibenzylideneacetone)palladium (0), tris(dibenzylideneacetone)dipalladium (0), bis(tri-tert-butylphosphine)palladium (0), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride.

Specific examples of the base include an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.

The reaction temperature is typically 0° C. to 150° C., preferably 25° C. to 100° C., but is not limited thereto. The reaction time is typically 1 hour to 72 hours, preferably 1 hour to 24 hours.

Step 9-2: Preparation Process of Compound (9-3)

Compound (9-3) is prepared from compound (9-1) according to the process of Step 2-1.

Step 9-3: Preparation Process of Compound (9-4)

Compound (9-4) is prepared by hydrogenating vinyl group in compound (9-3) with a metal catalyst in an appropriate solvent.

Examples of the metal catalyst include palladium/carbon, Raney nickel, platinum oxide/carbon, and rhodium/carbon.

The amount of the metal catalyst to be used for compound (9-2) is typically 0.1% by weight to 1000% by weight, preferably 1% by weight to 100% by weight.

Examples of the solvent include an alcohol such as methanol; an ether such as tetrahydrofuran; and an ester such as ethyl acetate.

The hydrogen pressure is typically 1 atm to 100 atms, preferably 1 atm to 5 atms.

The reaction temperature is typically 0° C. to 120° C., preferably 20° C. to 80° C., but is not limited thereto. The reaction time is typically 30 minutes to 72 hours, preferably 1 hour to 48 hours.

Compound (9-4) is also prepared by reacting compound (9-3) with hydrazine hydrate.

Preparation 10

One of the compounds of formula (1′), the compound of formula (10-4) is prepared according to, for example, the following process.

wherein W^(L), R¹, R², and ring Q¹ are as defined in the above [1]; X¹ and X² are as defined in the above [25]; R¹⁰¹ is C₁₋₆ alkyl group, R¹² is C₁₋₆ alkyl group, benzyl group, and allyl group; and R^(a) and R^(b) are independently the same or different hydrogen atom or methyl group.

Compound (10-1) may be prepared according to, for example, the process of Preparation 2.

Step 10-1: Preparation Process of Compound (10-2)

Compound (10-2) is prepared by reacting compound (10-1) with an aqueous alkaline solution.

Examples of the aqueous alkaline solution include aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, and aqueous lithium hydroxide solution, and the concentration thereof is typically 1-10 mol/L, preferably 1-5 mol/L.

Examples of the solvent used include methanol, ethanol, 2-propanol, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 10 minutes to 24 hours, preferably 30 minutes to 12 hours.

Step 10-2: Preparation Process of Compound (10-3)

Compound (10-3) is prepared from compounds (10-2) and (1-6) according to the process of Step 1-4.

Step 10-3: Preparation Process of Compound (10-4)

Compound (10-4) is prepared by reacting compound (10-3) with an aqueous alkaline solution.

Examples of the aqueous alkaline solution include aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, and aqueous lithium hydroxide solution, and the concentration thereof is typically 1-10 mol/L, preferably 1-5 mol/L.

Examples of the solvent used include methanol, ethanol, 2-propanol, THF, 1,4-dioxane, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 24 hours, preferably 1 hour to 6 hours.

Preparation 11

One of the compounds of formula (1′), the compound of formula (11-4) is prepared according to, for example, the following process.

wherein W¹, W³, R¹, R², R⁴, R⁵, n, ring Q¹, and ring Q² are as defined in the above [1]; and R¹⁰¹ is C₁₋₆ alkyl group.

Compound (11-1) may be a commercially available product or be prepared according to known synthesis processes (e.g. WO 2014/125444).

Step 11-1: Preparation Process of Compound (11-2)

Compound (11-2) is prepared by hydrolyzing compound (11-1) according to a similar process to a known process (e.g. Protective Groups in Organic Synthesis 3^(rd) Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by R. C. Larock, VCH publisher Inc., 1989).

Step 11-2: Preparation Process of Compound (11-4)

Compound (11-4) is prepared from compounds (11-2) and (11-3) according to the process of Step 1-4.

Preparation 12

One of the compounds of formula (1′), the compound of formula (12-5) is prepared according to, for example, the following process.

wherein W¹, R¹, R², R⁴, n, ring Q¹, and ring Q² are as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; and R^(c) and R^(d) are independently the same or different hydrogen atom, deuterium atom, or methyl group.

Step 12-1: Preparation Process of Compound (12-2)

Compound (12-2) is prepared by reacting compound (12-1) with haloacetate in an inert solvent in the presence of a base.

Specific examples of the haloacetate include tert-butyl chloroacetate, tert-butyl bromoacetate, and tert-butyl iodoacetate.

Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydride, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium diisopropylamide.

Examples of the inert solvent include DMF, THF, acetonitrile, and a mixture thereof.

The reaction temperature is typically 25° C. to 150° C., preferably 70° C. to 100° C., but is not limited thereto. The reaction time is typically 10 minutes to 12 hours, preferably 20 minutes to 6 hours.

Step 12-2: Preparation Process of Compound (12-3)

Compound (12-3) is prepared by cleaving tert-butylester group in compound (12-2) under an acid condition.

Examples of the acid used in the deprotection step include hydrochloric acid, sulfuric acid, HBr, HI, and TFA.

Examples of the solvent used include methanol, ethanol, dichloromethane, 1,2-dichloroethane, THF, 1,4-dioxane, ethyl acetate, a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 25° C. to 50° C., but is not limited thereto. The reaction time is typically 1 hour to 24 hours, preferably 2 hours to 12 hours.

Step 12-3: Preparation Process of Compound (12-4)

Compound (12-4) is prepared from compounds (12-3) and (1-6) according to the process of Step 1-4.

Step 12-4: Preparation Process of Compound (12-5)

Compound (12-5) is prepared from compound (12-4) according to the process of Step 8-2.

Preparation 13

The compound of formula (2-5) is also prepared from compound (2-1) according to, for example, the following process.

wherein R⁴, n, and ring Q² are as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; R^(a) and R^(b) are independently the same or different hydrogen atom or methyl group; A is boronic acid, boronate, BF₃K, or BF₃Na; R¹⁰³ is optionally-substituted phenyl group; and X is halogen atom.

Step 13-1: Preparation Process of Compound (13-2)

Compound (13-2) is prepared by reacting compound (2-1) with compound (13-1) in an inert solvent in the presence of a palladium catalyst and a base.

Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium (0), bis(dibenzylideneacetone)palladium (0), tris(dibenzylideneacetone)dipalladium (0), bis(tri-tert-butylphosphine)palladium (0), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride.

Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, and potassium hydroxide.

Examples of the inert solvent include 1,4-dioxane, THF, 1,2-dimethoxyethane, water, and a mixture thereof.

The reaction temperature is typically 50° C. to 200° C., preferably 80° C. to 150° C., but is not limited thereto. The reaction time is typically 1 hour to 48 hours, preferably 6 hours to 18 hours.

Step 13-2: Preparation Process of Compound (2-5)

Compound (2-5) is prepared by hydrogenating benzyl group in compound (13-2) with a metal catalyst in an appropriate solvent to cleave the group.

Examples of the metal catalyst include palladium/carbon, Raney nickel, platinum oxide/carbon, and rhodium/carbon.

The amount of the metal catalyst to be used for compound (13-2) is typically 0.1% by weight to 1000% by weight, preferably 1% by weight to 100% by weight.

Examples of the solvent include an alcohol such as methanol; an ether such as tetrahydrofuran; and an ester such as ethyl acetate.

The hydrogen pressure is typically 1 atm to 100 atms, preferably 1 atm to 5 atms.

The reaction temperature is typically 0° C. to 120° C., preferably 20° C. to 80° C., but is not limited thereto. The reaction time is typically 30 minutes to 72 hours, preferably 1 hour to 48 hours.

Also, when R¹⁰³ is phenyl group substituted with group(s) such as 4-methoxy group and 2,4-dimethoxy group, compound (2-5) is prepared by reacting compound (13-2) with an acid.

Examples of the acid include TFA, formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and (±) 10-camphorsulfonic acid.

Examples of the solvent used include dichloromethane, 1,2-dichloroethane, 1,4-dioxane, THF, toluene, ethyl acetate, methanol, ethanol, 2-propanol, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 25° C. to 50° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 9 hours.

Preparation 14 One of the compounds of formula (1′), the compound of formula (14-3) is prepared according to, for example, the following process.

wherein W¹, R¹, R², R⁴, n, ring Q¹, and ring Q² are as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; R^(a) and R^(b) are independently the same or different hydrogen atom or methyl group; and R¹⁰³ is optionally-substituted phenyl group.

Step 14-1: Preparation Process of Compound (14-1)

Compound (14-1) is prepared by hydrolyzing compound (13-2) according to a similar process to a known process (e.g. Protective Groups in Organic Synthesis 3^(rd) Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by R. C. Larock, VCH publisher Inc., 1989). In this case, compound (14-1) may be also used in the next reaction without any isolation.

For example, compound (13-2) is hydrolyzed according to the above process to neutralize the reaction solution and then the solvent is removed to give compound (14-1), and the resulting compound may be used in Step 14-2.

Step 14-2: Preparation Process of Compound (14-2)

Compound (14-2) is prepared from compounds (14-1) and (1-6) according to the process of Step 1-4.

Step 14-3: Preparation Process of Compound (14-3)

Compound (14-3) is prepared by hydrogenating benzyl group in compound (14-2) with a metal catalyst in an appropriate solvent to cleave the group.

Examples of the metal catalyst include palladium/carbon, Raney nickel, platinum oxide/carbon, and rhodium/carbon.

The amount of the metal catalyst to be used for compound (14-2) is typically 0.1% by weight to 1000% by weight, preferably 1% by weight to 100% by weight.

Examples of the solvent include an alcohol such as methanol; an ether such as tetrahydrofuran; and an ester such as ethyl acetate.

The hydrogen pressure is typically 1 atm to 100 atms, preferably 1 atm to 5 atms.

The reaction temperature is typically 0° C. to 120° C., preferably 20° C. to 80° C., but is not limited thereto. The reaction time is typically 30 minutes to 72 hours, preferably 1 hour to 48 hours.

Also, when R¹⁰³ is phenyl group substituted with group(s) such as 4-methoxy group and 2,4-dimethoxy group, compound (14-3) is prepared by reacting compound (14-2) with an acid.

Examples of the acid include TFA, formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and (±) 10-camphorsulfonic acid.

Examples of the solvent used include dichloromethane, 1,2-dichloroethane, 1,4-dioxane, THF, toluene, ethyl acetate, methanol, ethanol, 2-propanol, and a mixture thereof.

The reaction temperature is typically 0° C. to 100° C., preferably 25° C. to 50° C., but is not limited thereto. The reaction time is typically 30 minutes to 12 hours, preferably 1 hour to 9 hours.

Preparation 15

One of the compounds of formula (1′), the compound of formula (14-2) is prepared according to, for example, the following process.

wherein W¹, R¹, R², R⁴, n, ring Q¹, and ring Q² are as defined in the above [1]; R¹⁰¹ is C₁₋₆ alkyl group; R^(d) and R^(b) are independently the same or different hydrogen atom or methyl group; X is halogen atom; A is boronic acid, boronate, BF₃K, or BF₃Na; and R¹⁰³ is optionally-substituted phenyl group.

Step 15-1: Preparation Process of Compound (15-1)

Compound (15-1) is prepared by hydrolyzing compound (2-1) according to a similar process to a known process (e.g. Protective Groups in Organic Synthesis 3^(rd) Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by R. C. Larock, VCH publisher Inc., 1989).

In this case, compound (15-1) may be also used in the next reaction without any isolation.

For example, compound (2-1) is hydrolyzed according to the above process to neutralize the reaction solution and then the solvent is removed to give compound (15-1), and the resulting compound may be used in Step 15-2.

Step 15-2: Preparation Process of Compound (15-2)

Compound (15-2) is prepared from compounds (15-1) and (1-6) according to the process of Step 1-4.

Step 15-3: Preparation Process of Compound (14-2)

Compound (14-2) is prepared by reacting compound (15-2) with compound (13-1) in an inert solvent in the presence of a palladium catalyst and a base.

Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium (0), bis(dibenzylideneacetone)palladium (0), tris(dibenzylideneacetone)dipalladium (0), bis(tri-tert-butylphosphine)palladium (0), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride.

Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, and potassium hydroxide.

Examples of the inert solvent include 1,4-dioxane, THF, 1,2-dimethoxyethane, water, and a mixture thereof.

The reaction temperature is typically 50° C. to 200° C., preferably 80° C. to 150° C., but is not limited thereto. The reaction time is typically 1 hour to 48 hours, preferably 6 hours to 18 hours.

Preparation 16

One of the compounds of formula (1′), the compound of formula (1-7) is prepared according to, for example, the following process.

wherein W¹, W³, R¹, R², R⁴, R⁵, n, ring Q¹, and ring Q² are as defined in the above [1]; R¹⁰² is protective group; and L is a leaving group (such as iodine atom, bromine atom, chlorine atom, and substituted sulfonyloxy group (such as methanesulfonyloxy group and p-toluenesulfonyloxy group)).

Step 16-1: Preparation Process of Compound (16-1)

Compound (16-1) is prepared by introducing a protective group into nitrogen atom in the 1-position of imidazole group in compound (1-3) in an inert solvent. Examples of the protective group include 2-(trimethylsilyl)ethoxymethyl, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl.

For example, when 2-(trimethylsilyl)ethoxymethyl group is introduced, compound (16-1) is prepared by reacting compound (1-3) with 2-(trimethylsilyl)ethoxymethyl chloride in an inert solvent in the presence of a base.

Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydride, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium diisoproylamide.

Examples of the inert solvent include DMF, THF, acetonitrile, and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 0° C. to 100° C., but is not limited thereto. The reaction time is typically 10 minutes to 24 hours, preferably 20 minutes to 6 hours.

Step 16-2: Preparation Process of Compound (16-2)

Compound (16-2) is prepared from compound (16-1) according to the process of Step 1-3.

Step 16-3: Preparation Process of Compound (16-3)

Compound (16-3) is prepared from compounds (16-2) and (1-2) according to the process of Step 1-4.

Step 16-4: Preparation Process of Compound (16-4)

Compound (16-4) is prepared by cleaving the protective group in nitrogen atom of imidazole group in compound (16-3) in an inert solvent.

For example, when 2-(trimethylsilyl)ethoxymethyl group is cleaved, compound (16-4) is prepared by reacting compound (16-3) with an acid or a fluorinating reagent.

Examples of the acid include TFA, formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and (±) 10-camphorsulfonic acid.

Examples of the fluorinating reagent include tetrabutylammonium fluoride.

Examples of the solvent used include dichloromethane, 1,2-dichloroethane, 1,4-dioxane, THF, toluene, ethyl acetate, methanol, ethanol, 2-propanol, and a mixture thereof.

The reaction temperature is typically 0° C. to 150° C., preferably 0° C. to 50° C., but is not limited thereto. The reaction time is typically 5 minutes to 24 hours, preferably 1 hour to 9 hours.

Step 16-5: Preparation Process of Compound (1-7)

Compound (1-7) is prepared from compounds (16-4) and (1-4) according to the process of Step 1-2.

The intermediates and desired compounds in the above preparations may be isolated and purified by a conventional purification method in organic synthetic chemistry such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and each type of chromatography. The intermediates may be also used in the next reaction without any specific purification.

An optically-active product of the present compound can be prepared from an optically-active starting material or intermediate, or by the optical resolution of the racemate of a final product. The optical resolution method includes a physical separation method with optically-active column, and a chemical separation method such as a fractional crystallization method. A diastereomer of the present compound can be prepared by, for example, a fractional crystallization method.

The pharmaceutically acceptable salt of the compound of formula (1′) can be prepared by, for example, mixing the compound of formula (1′) with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, and acetone.

The present compound is used as, for example, an anti-tumor agent (anti-cancer agent). The applicable cancer type includes hematopoietic tumor and solid cancer, but is not limited thereto. Specific examples of the hematopoietic tumor include acute leukemia, chronic lymphatic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, and myeloma, and specific examples of the solid cancer include brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small-cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder or bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, chorioepithelioma, endometrial cancer, cervical cancer, urothelial cancer, renal cell cancer, prostate cancer, testicular tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma.

The anti-tumor agent is used for the prophylaxis and/or treatment of a cancer, and is expected to produce the reduction or disappearance of carcinoma or inhibit the growth of carcinoma down to a certain level. The “prophylaxis” used herein means the administration of the active ingredient of the present invention to a healthy subject who does not develop a disease. For example, the prophylaxis is intended to prevent the development of a disease. The “treatment” used herein means the administration of the active ingredient of the present invention to a person diagnosed with the development of a disease by a doctor (i.e. a patient). For example, the treatment is intended to alleviate a disease or symptom thereof, inhibit the growth of carcinoma, or improve the condition of a patient to the previous condition before a disease is developed. Also, even if an anti-tumor agent is administered for the purpose of preventing the worsening of a disease or symptom thereof or the growth of carcinoma, the administration is referred to as “treatment” when the subject to be administered is a patient.

The present compound has any remarkable effects for inhibiting self-renewal ability of CSCs, and thus is expected to be useful as a novel anti-tumor agent for inhibiting the persistent proliferation, metastasis, and recurrence of malignant tumors derived from CSCs.

The present compound may be formulated into a suitable dosage form and administered orally or parenterally. Examples of the dosage form include a tablet, a capsule, a powder, a granule, a solution, a suspension, an injection, a patch, and a poultice, but are not limited thereto. The preparation is formulated using pharmaceutically acceptable additive(s) according to a known method.

As appropriate, an additive such as an excipient, a disintegrant, a binder, a fluidizer, a lubricant, a coating agent, a solubilizer, a solubilizing agent, a thickening agent, a dispersant, a stabilizing agent, a sweetening agent, and a flavor may be used. Specific examples thereof include lactose, mannitol, crystalline cellulose, low substituted hydroxypropylcellulose, corn starch, partly pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylalcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

The present compound may be used in combination with another drug(s) to enhance the therapeutic effect thereof and/or reduce side effects thereof. Specifically, the present compound can be used in combination with a drug such as a hormone therapeutic drug, a chemotherapeutic drug, an immunotherapeutic drug or a cell growth factor and a drug for inhibiting a receptor effect thereof. Hereinafter, a drug which can be used in combination with the present compound is referred to as “combined medicine”.

Examples of the combined medicine include an anti-cancerous alkylating agent, an anti-cancerous antimetabolite, an anti-cancerous antibiotic, a plant-based anti-cancer agent, an anti-cancerous platinum coordination compound, an anti-cancerous camptothecin derivative, an anti-cancerous tyrosine kinase inhibitor, a serine-threonine kinase, a phospholipid kinase, a monoclonal antibody, an interferon, a biological response modifier, a hormone preparation, an immune checkpoint inhibitor, an epigenetics-related molecule inhibitor, a post-translational protein modification inhibitor, and other anti-cancer agents.

The administration timing of the present compound and a combined medicine is not necessarily limited, and they may be administered simultaneously or administered with time-interval to a subject. In addition, the present compound and a combined medicine may be used in the form of a combination drug. The dosage of the combined medicine may be optionally determined based on the dosage in the clinical use. Also, the mixing ratio of the present compound and a combined medicine may be optionally determined depending on the subject to be administered, the administration route, the disease to be treated, the symptom, and a combination thereof. For example, when the subject is human, the combined medicine may be used in an amount of 0.01 to 100 parts by weight relative to 1 part by weight of the present compound. In addition, a drug (a combined medicine) such as an antiemetic, a sleep inducing agent, and an anticonvulsant may be used in combination with the present compound to inhibit side effects thereof.

The dosage can vary according to each compound and various conditions such as patient's disease, age, body weight, sex, symptom, and administration route. Typically, the present compound is administered to an adult (body weight: 50 kg) at a dose of 0.1 to 1000 mg/day, preferably at a dose of 0.1 to 300 mg/day, which may be administered once a day or 2 or 3 times a day. In addition, the present compound may be administered once in several days to several weeks.

EXAMPLES

Hereinafter, the invention is illustrated in more detail with Reference Examples, Examples, and Test Examples, but the invention should not be limited thereto. The compound names as shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature system.

The following abbreviations may be used herein.

THF: tetrahydrofuran TFA: trifluoroacetic acid (Boc)₂O: di-tert-butyl dicarbonate DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

DMF: N,N-dimethylformamide

DME: 1,2-dimethoxyethane

DIEA: N,N-diisopropylethylamine

DMAP: N,N-dimethyl-4-aminopyridine EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDCI.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole HOBt.H₂O: 1-hydroxybenzotriazole monohydrate

NBS: N-bromosuccinimide

TBSCl: tert-butyldimethylchlorosilane Me: methyl Et: ethyl Ac: acetyl Boc: tert-butoxycarbonyl SEM: 2-(trimethylsilyl)ethoxymethyl Rt: retention time

LC/MS analysis condition in the compound identification is as follows.

LC/MS Measurement:

Detection device: ACQUITY® SQ deteceter (Waters) HPLC: ACQUITY UPLC® system Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm×30 mm) Solvent: A solution: 0.06% formic acid/H₂O, B solution: 0.06% formic acid/MeCN Gradient condition: 0.0-1.3 min Linear gradient from B 2% to 96% Flow rate: 0.8 mL/min

UV: 220 nm and 254 nm Reference Example 1 4-Nitro-1-[3-(trifluoromethyl)benzyl]-1H-imidazole

A mixture of 4-nitro-1H-imidazole (35.8 g), 3-trifluoromethylbenzyl bromide (75.7 g), potassium iodide (0.131 g), potassium carbonate (48.1 g), and acetonitrile (270 mL) was stirred at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, and then water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo. To the resulting solid was added diisopropyl ether (300 mL), and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected on a filter, washed with diisopropyl ether, and dried at 50° C. in vacuo to give the title compound (69.0 g).

LC-MS ([M+H]⁺/Rt (min)): 272.1/0.835

Reference Examples 2-3

According to the process of Reference Example 1, the compounds of Reference Examples 2-3 were prepared from each corresponding starting compound.

LC-MS: Reference [M + H]⁺/ Examples chemical structural formula Rt (min) 2

238.1/0.776 3

258.1/0.742

Reference Example 4 1-[3-(Trifluoromethyl)benzyl]-1H-imidazole-4-amine hydrochloride

To the compound of Reference Example 1 (34.0 g) and rhodium-activated carbon (5%, 17.0 g) was added ethyl acetate (330 mL), and the mixture was stirred at room temperature under hydrogen atmosphere for 14 hours. The reaction mixture was filtered through Celite®, washed with ethyl acetate (50 mL×4), and then to the filtrate was added hydrogen chloride (4 mol/L in ethyl acetate, 38.0 mL). The filtrate was concentrated in vacuo, and then to the resulting crude product were added ethyl acetate (200 mL) and hexane (200 mL), and the mixture was stirred at room temperature for 10 minutes. The resulting precipitate was collected on a filter and washed with hexane/ethyl acetate (1/1, 20 mL×3), and then the resulting solid was dried at 40° C. in vacuo to give the title compound (31.4 g).

LC-MS ([M+H]⁺/Rt (min)): 242.1/0.548

Reference Examples 5-6

According to the process of Reference Example 4, the compounds of Reference Examples 5-6 were prepared from each corresponding starting compound.

LC-MS: Reference [M + H]⁺/ Examples chemical structural formula Rt (min) 5

208.1/0.460 6

228.1/0.473

Reference Example 7 Methyl 6-({1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}carbamoyl)nicotinate

To a suspension of the compound of Reference Example 4 (300 mg) in DMF (5 mL) were added 5-(methoxycarbonyl)picolinic acid (235 mg), EDCI.HCl (248 mg), HOBt (175 mg), and N,N-diisopropylethylamine (0.279 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (281 mg).

LC-MS ([M+H]⁺/Rt (min)): 404.9/0.901

Reference Examples 8-19

According to the process of Reference Example 7, the compounds of Reference Examples 8-19 were prepared from each corresponding starting compound.

Reference LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min)  8

404.9/0.780  9

443.1/0.960 10

415.2/0.992 11

503.1/1.017 12

411.2/0.897 13

395.2/0.863 14

395.2/0.888 15

415.1/0.915 16

431.1/0.942 17

415.1/0.849 18

489.0/0.991 19

401.0/0.967

Reference Example 20 6-Ethenyl-5-fluoro-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Reference Example 9 (300 mg) in a mixture of 1,4-dioxane (5 mL)/water (0.5 mL) were added vinylboronic acid pinacol ester (0.232 mL), tetrakis(triphenylphosphine)palladium (78 mg), and potassium carbonate (281 mg), and the mixture was stirred under microwave irradiation at 120° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol) to give the title compound (122 mg).

LC-MS ([M+H]⁺/Rt (min)): 391.2/0.936

Reference Examples 21-30

According to the process of Reference Example 20, the compounds of Reference Examples 21-30 were prepared from each corresponding starting compound.

Reference LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 21

407.2/1.004 22

451.2/1.017 23

403.3/0.895 24

387.2/0.767 25

387.2/0.815 26

407.2/0.894 27

379.2/0.897 28

363.2/0.834 29

437.1/0.989 30

393.2/0.976

Reference Example 31 6-Ethenyl-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide

To a solution of the compound of Reference Example 29 (200 mg) in THF (4 mL) were added bis(tri-tert-butylphosphine)palladium (0) (23 mg) and methylzinc chloride (2 mol/L in THF, 0.69 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (135 mg).

LC-MS ([M+H]⁺/Rt (min)): 373.2/0.824

Reference Example 32 6-(1,2-Dihydroxyethyl)-5-methoxy-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Reference Example 23 (490 mg) in acetone (5 mL)/water (2.5 mL) were added N-methylmorpholine-N-oxide (285 mg) and osmium tetroxide (2.5 wt % in tert-butanol, 0.764 mL), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture were then added saturated aqueous sodium thiosulfate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (142 mg).

LC-MS ([M+H]⁺/Rt (min)): 437.3/0.684

Reference Examples 33-38

According to the process of Reference Example 32, the compounds of Reference Examples 33-38 were prepared from each corresponding starting compound.

Reference LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 33

421.2/0.642 34

421.2/0.656 35

441.2/0.710 36

397.2/0.647 37

471.2/0.702 38

407.2/0.612

Reference Example 39-1 6-(Chloromethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a suspension of the compound of Example 12 (400 mg) in THF were added lithium chloride (90 mg), N,N-diisopropylethylamine (0.366 mL) and then methanesulfonyl chloride (0.165 mL), and the mixture was stirred at room temperature for 4 hours. Lithium chloride (45 mg), N,N-diisopropylethylamine (0.183 mL), and methanesulfonyl chloride (0.083 mL) were added thereto, and then the mixture was additionally stirred at room temperature for 17 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (269 mg).

LC-MS ([M+H]⁺/Rt (min)): 395.2/0.835

Reference Example 39-2 6-[(Di-tert-butoxycarbonyl)aminomethyl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of di-tert-butyl iminodicarbonate (586 mg) in DMF (3 mL) was added sodium hydride (118 mg), and the mixture was stirred at room temperature for 25 minutes. To the reaction mixture was added a solution of the compound of Reference Example 39-1 obtained by the above process (213 mg) in DMF (6 mL), and the mixture was stirred at room temperature for 2 hours and then at 50° C. for 4 hours. The mixture was cooled to room temperature, and to the reaction mixture was added saturated aqueous ammonium chloride solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (119 mg).

LC-MS ([M+H]⁺/Rt (min)): 576.5/1.080

Reference Example 40 Ethyl 6-(ethoxymethyl)-nicotinate

To ethanol (20 mL) was added sodium (237 mg) over 1 hour, and ethyl 6-(bromomethyl)-nicotinate (500 mg) was added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove the ethanol, and saturated aqueous sodium hydrogen carbonate solution was added thereto, and then the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (159 mg).

LC-MS ([M+H]⁺/Rt (min)): 210.3/0.800

Reference Example 41-1 Methyl 5-[(tert-butoxycarbonyl)amino]-6-chloro-nicotinate

To a solution of methyl 5-amino-6-chloro-nicotinate (325 mg) in THF (10 mL) were added di-tert-butyl dicarbonate (760 mg) and DMAP (11 mg), and the mixture was stirred at room temperature for 15.5 hours. Additional di-tert-butyl dicarbonate (38 mg) was added thereto, and the mixture was stirred at 60° C. for 45 minutes. The mixture was cooled to room temperature, and then the solvent was removed. To the residue were added methanol (5 mL) and potassium carbonate (481 mg), and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (321 mg).

LC-MS ([M+H]⁺/Rt (min)): 287.1/0.985

Reference Example 41-2 Methyl 5-[(tert-butoxycarbonyl)amino]-6-ethenyl-nicotinate

According to the process of Reference Example 20, the title compound was prepared from the compound of Reference Example 41-1.

LC-MS ([M+H]⁺/Rt (min)): 279.5/0.885

Reference Example 41-3 Methyl 5-[(tert-butoxycarbonyl)amino]-6-formyl-nicotinate

To a solution of the compound of Reference Example 41-2 (207 mg) in a mixture of acetone (8 mL)/water (4 mL) were added sodium periodate (659 mg) and osmium tetroxide (2.5 wt % in tert-butanol, 0.71 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were then added saturated aqueous sodium thiosulfate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (110 mg).

LC-MS ([M+H]⁺/Rt (min)): 281.2/1.037

Reference Example 41-4 Methyl 5-[(tert-butoxycarbonyl)amino]-6-(hydroxymethyl)-nicotinate

To a solution of the compound of Reference Example 41-3 (110 mg) in methanol was added sodium borohydride (15 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were then added saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (111 mg).

LC-MS ([M+H]⁺/Rt (min)): 282.8/0.761

Reference Example 41-5 2-Oxo-1,4-dihydro-2H-pyrido[3,2-d] [1,3]oxazine-7-carboxylic acid

To a solution of the compound of Reference Example 41-4 (111 mg) in THF (2 mL)/methanol (4 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.39 mL), and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added 2 mol/L hydrochloride (0.25 mL) to adjust pH to 7. The reaction mixture was concentrated in vacuo to give the title compound (76 mg).

LC-MS ([M+H]⁺/Rt (min)): 195.1/0.325

Reference Example 41-6 2-Oxo-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazine-7-carboxamide

According to the process of Reference Example 7, the title compound was prepared from the compounds of Reference Examples 41-5 and 4.

LC-MS ([M+H]⁺/Rt (min)): 418.2/0.711

Reference Example 42 2-Oxo-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazine-7-carboxamide

According to the process of Reference Example 7, the title compound was prepared from the compounds of Reference Examples 41-5 and 6.

LC-MS ([M+H]⁺/Rt (min)): 404.2/0.670

Reference Example 43-1 Methyl 6-chloro-5-(dibromomethyl)-nicotinate

To a suspension of methyl 6-chloro-5-methyl-nicotinate (467 mg) in carbon tetrachloride (25 mL) were added N-bromosuccinimide (1.34 g) and benzoyl peroxide (218 mg), and the mixture was stirred at 100° C. for 7.5 hours. The mixture was cooled to room temperature, and to the reaction mixture were added saturated aqueous sodium thiosulfate solution and water, and then the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (833 mg).

LC-MS ([M+H]⁺/Rt (min)): 341.9/1.011

Reference Example 43-2 Methyl 6-chloro-5-formyl-nicotinate

To a solution of the compound of Reference Example 43-1 (2.71 g) in acetonitrile (40 mL)/water (20 mL) was added silver nitrate (6.70 g), and the mixture was stirred at 100° C. for 3 hours. The insoluble product was removed by filtration, and the solvent was removed. To the residue was added saturated aqueous sodium hydrogen carbonate solution to adjust pH to 8, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (0.84 g).

LC-MS ([M+H]⁺/Rt (min)): 200.0/0.671

Reference Example 43-3 Methyl 6-chloro-5-(difluoromethyl)-nicotinate

To a solution of the compound of Reference Example 43-2 (0.84 g) in dichloromethane (20 mL) was added DAST (1.11 mL) with ice-cooling, and the mixture was stirred with ice-cooling for 30 minutes. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution to adjust pH to 8, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.45 g).

LC-MS ([M+H]⁺/Rt (min)): 222.0/0.828

Reference Example 43-4 Methyl 5-(difluoromethyl)-6-(hydroxymethyl)-nicotinate

According to the processes of Reference Examples 20, 41-3, and 41-4, the title compound was prepared from the compound of Reference Example 43-3.

LC-MS ([M+H]⁺/Rt (min)): 218.1/0.564

Reference Example 44 Methyl 6-(hydroxymethyl)-5-(trifluoromethyl)-nicotinate

According to the processes of Reference Examples 20, 41-3, and 41-4, the title compound was prepared from methyl 6-chloro-5-(trifluoromethyl)-nicotinate.

LC-MS ([M+H]⁺/Rt (min)): 236.1/0.649

Reference Example 45-1 Methyl 5-(2-tert-butoxy-2-oxoethoxy)-picolinate

To a solution of methyl 5-hydroxy-picolinate (200 mg) in DMF (5 mL) were added potassium carbonate (361 mg) and tert-butyl bromoacetate, and the mixture was stirred at 70° C. for 20 minutes. The mixture was cooled to room temperature, and to the reaction mixture was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine twice, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (320 mg).

LC-MS ([M+H]⁺/Rt (min)): 268.2/0.777

Reference Example 45-2 {[6-(Methoxycarbonyl)pyridin-3-yl]oxy}acetic acid

To a solution of the compound of Reference Example 45-1 (320 mg) in dichloromethane (4 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed to give the title compound (253 mg).

LC-MS ([M+H]⁺/Rt (min)): 212.1/0.394

Reference Example 45-3 Methyl 5-(2-oxo-2-{[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]amino}ethoxy)-picolinate

According to the process of Reference Example 7, the title compound was prepared from the compounds of Reference Example 45-2 and 6.

LC-MS ([M+H]⁺/Rt (min)): 421.2/0.731

Reference Example 46-1 4-({[Tert-butyl(dimethyl)silyl]oxy}methyl-1,3-thiazole-2-carboxylic acid

To a solution of (2-bromo-5-methyl-1,3-thiazol-4-yl)methanol (151 mg) in DMF (3 mL) was added imidazole (59 mg) and TBSCl (131 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were then added saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2-bromo-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-methyl-1,3-thiazole.

To a solution of the resulting 2-bromo-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-methyl-1,3-thiazole in THF (4 mL) was added n-butyllithium (0.91 mL) at −78° C., and the mixture was stirred at this temperature for 1 hour. An excess amount of powdered dry ice was then added thereto, and the mixture was stirred at this temperature for 45 minutes and then at room temperature for 40 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (127 mg).

LC-MS ([M+H]⁺/Rt (min)): 288.1/1.058

Reference Example 46-2 4-({[Tert-butyl(dimethyl)silyl]oxy}methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,3-thiazole-2-carboxamide

According to the process of Reference Example 7, the title compound was prepared from the compounds of Reference Examples 46-1 and 6.

LC-MS ([M+H]⁺/Rt (min)): 497.1/1.314

Reference Example 47 5-({[Tert-butyl(dimethyl)silyl]oxy}methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,3-thiazole-2-carboxamide

According to the processes of Reference Examples 46-1 and 7, the title compound was prepared from the corresponding starting compound.

LC-MS ([M+H]⁺/Rt (min)): 497.1/1.333

Reference Example 48 6-Formyl-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a suspension of the compound of Example 12 (200 mg) in dichloromethane (10 mL) was added manganese dioxide (2 g), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was filtered through Celite®, and the filter cake was washed with ethyl acetate and methanol. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (55 mg).

LC-MS ([M+H]⁺/Rt (min)): 375.2/0.793

Reference Example 49-1 Methyl 1-(3,4,5-trifluorobenzyl-1H-imidazole-4-carboxylate

To a solution of methyl 1H-imidazole-4-carboxylate (14.0 g) in acetonitrile (200 mL) were added potassium carbonate (19.9 g) and potassium iodide (0.092 g), and 3,4,5-trifluorobenzyl bromide (14.6 mL) was added dropwise thereto at room temperature, and then the mixture was stirred at 70° C. for 6 hours. The mixture was cooled to room temperature, and to the reaction mixture was added water, and then the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The resulting crude product was washed with hexane/ethyl acetate (1/2, 60 mL) to give the title compound (14.0 g).

LC-MS ([M+H]⁺/Rt (min)): 271.4/0.725

Reference Example 49-2 1-(3,4,5-Trifluorobenzyl)-1H-imidazole-4-carboxylic acid

To a solution of the compound of Reference Example 49-1 (4.75 g) in methanol/THF (50 mL/50 mL) was added 2 mol/L aqueous sodium hydroxide solution (13.2 mL), and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water, and then aqueous hydrochloric acid solution was added thereto to adjust pH to 5. The resulting precipitate was collected on a filter, washed with water and hexane, and then dried at 50° C. in vacuo to give the title compound (4.52 g).

LC-MS ([M+H]⁺/Rt (min)): 257.1/0.513

Reference Example 50 6-({[Tert-butyl(dimethyl)silyl]oxy}methyl)pyridine-3-amine

To a solution of (5-aminopyridin-2-yl)methanol (135 mg) in THF (15 mL) were added triethylamine (0.30 mL) and TBSCl (328 mg), and the mixture was stirred at room temperature for 6 hours. The solvent was removed in vacuo, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (99 mg).

LC-MS ([M+H]⁺/Rt (min)): 239.2/0.726

Reference Example 51 2-({[Tert-butyl (dimethyl) silyl]oxy}methyl)quinoline-6-amine

According to the process of Reference Example 50, the title compound was prepared from (6-aminoquinolin-2-yl)methanol.

LC-MS ([M+H]⁺/Rt (min)): 289.9/0.836

Reference Examples 52-53

According to the process of Reference Example 7, the compounds of Reference Examples 52-53 were prepared from the compound of Reference Example 49 and each corresponding starting compound.

Reference LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 52

527.3/1.289 53

411.2/0.915

Reference Example 54 Methyl 6-(3-hydroxyprop-1-en-2-yl)nicotinate

To a solution of methyl 6-methylnicotinate (420 mg) in water (2 mL) were added triethylamine (0.065 mL) and paraformaldehyde (42 mg), and the mixture was stirred under microwave irradiation at 150° C. for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (24 mg).

LC-MS ([M+H]⁺/Rt (min)): 194.1/0.532

¹H-NMR (400 MHz, CDCl₃): δ 9.15-9.13 (1H, m), 8.29 (1H, dd, J=8.4, 2.0 Hz), 7.70 (1H, d, J=8.4 Hz), 5.94 (1H, s), 5.65 (1H, s), 4.61 (2H, s), 3.97 (3H, s).

Reference Example 55 Methyl 6-[(1E)-3-hydroxyprop-1-en-1-yl]nicotinate

To a solution of (2E)-3-[5-(methoxycarbonyl)pyridin-2-yl]prop-2-enoic acid (50 mg) in DME (1 mL) were added N-methylmorpholine (0.056 mL) and isobutyl chloroformate (0.035 mL), and the mixture was stirred at 0° C. for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated to give a crude product of mixed anhydrate.

To a suspension of sodium borohydride (23.3 mg) in THF/water (2 mL/0.5 mL) was added a solution of the resulting mixed anhydrate in THF at 0° C. The reaction solution was stirred at room temperature for 3 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (19 mg).

LC-MS ([M+H]⁺/Rt (min)): 194.3/0.741

Reference Example 56-1 Methyl 6-(oxiran-2-yl)-nicotinate

To a solution of ethyl 6-ethenyl-nicotinate (210 mg) in tert-butylalcohol/water (6 mL/3 mL) was added NBS (232 mg), and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched with aqueous sodium hydroxide solution in an ice bath, and the reaction solution was neutralized with hydrochloric acid, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo.

The residue was dissolved in THF (10 mL), and sodium hydride (78 mg) was added thereto in an ice bath, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125.3 mg).

LC-MS ([M+H]⁺/Rt (min)): 194.1/0.654

Reference Example 56-2 Ethyl 6-(2-hydroxyethyl)-nicotinate

To a solution of the compound of Reference Example 56-1 (125 mg) in ethanol (10 mL) were added 5% palladium/carbon (138 mg) and ammonium formate (204 mg), and the mixture was stirred at 50° C. for 3 hours. The palladium was filtered through Celite®, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (87.3 mg)

LC-MS ([M+H]⁺/Rt (min)): 196.1/0.467

¹H-NMR (400 MHz, CDCl₃): δ 9.12 (1H, d, J=2.4 Hz), 8.23 (1H, dd, J=8.0, 2.4 Hz), 7.26 (1H, d, J=8.0 Hz), 4.41 (2H, q, J=7.6 Hz), 4.06-4.03 (2H, m), 3.11-3.07 (2H, m), 1.41 (3H, t, J=7.6 Hz).

Reference Example 57 Methyl 5-(hydroxymethyl)pyrazine-2-carboxylate

According to the processes of Reference Examples 20, 41-3, and 41-4, the title compound was prepared from methyl 5-chloropyrazine-2-carboxylate.

LC-MS ([M+H]⁺/Rt (min)): 169.0/0.334

Reference Example 58 6-({Methyl[(2-nitrophenyl)sulfonyl]amino}methyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Example 12 (101 mg) in chloroform (4 mL) were added N-methyl-2-nitrobenzenesulfonamide (79 mg), diethyl azodicarboxylate (2.2 mol/L toluene solution, 159 μL), and triphenylphosphine (92 mg), and the mixture was stirred at room temperature for 20 hours. N-methyl-2-nitrobenzenesulfonamide (80 mg), diethyl azodicarboxylate (2.2 mol/L toluene solution, 159 μL), and triphenylphosphine (93 mg) were additionally added thereto, and the mixture was stirred at 60° C. for 6 hours. N-methyl-2-nitrobenzenesulfonamide (157 mg), diethyl azodicarboxylate (2.2 mol/L toluene solution, 318 μL), and triphenylphosphine (194 mg) were additionally added thereto, and the mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (174 mg).

LC-MS ([M+H]⁺/Rt (min)): 575.3/0.944

Reference Example 59-1 Methyl 5-ethenyl-6-hydroxy-nicotinate

According to the process of Reference Example 20, the title compound was prepared from methyl 5-bromo-6-hydroxynicotinate.

LC-MS ([M+H]⁺/Rt (min)): 180.0/0.541

Reference Example 59-2 Methyl 6-chloro-5-ethenyl-nicotinate

To a suspension of the compound of Reference Example 59-1 (1.37 g) in phosphorous oxychloride (14.3 mL) was stirred at 90° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (1.45 g).

LC-MS ([M+H]⁺/Rt (min)): 198.0/0.870

Reference Example 59-3 Methyl 6-chloro-5-formyl-nicotinate

According to the process of Reference Example 41-3, the title compound was prepared from the compound of Reference Example 59-2.

LC-MS ([M+H]⁺/Rt (min)): 200.0/0.671

Reference Example 60-1 Isopropyl 5-bromo-6-chloro-nicotinate

A suspension of 5-bromo-6-hydroxy-nicotinic acid (10 g) in thionyl chloride (17 mL)/DMF (0.36 mL) was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the residue was then added 2-propanol (25 mL), and the mixture was stirred at 100° C. for 40 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the residue were then added saturated aqueous sodium carbonate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (12.4 g).

LC-MS ([M+H]⁺/Rt (min)): 278.0/1.102

Reference Example 60-2 Isopropyl 6-chloro-5-formyl-nicotinate

To a solution of the compound of Reference Example 60-1 (2.0 g) in THF (30 mL) was cooled to −20° C., and isopropylmagnesium chloride lithium chloride complex (1.3 mol/L in THF, 7.2 mL) was added thereto, and then the reaction mixture was stirred at −20° C. for 35 minutes. Isopropylmagnesium chloride lithium chloride complex (1.3 mol/L in THF, 0.55 mL) was added thereto, and the mixture was additionally stirred at −20° C. for 25 minutes. DMF (1.11 mL) was added thereto, and the reaction mixture was stirred at room temperature for 1 hour 10 minutes. Saturated aqueous ammonium chloride solution and water were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to give the title compound (1.64 g).

LC-MS ([M+H]⁺/Rt (min)): 228.1/0.897

Reference Example 60-3 Isopropyl 6-chloro-5-(difluoromethyl)-nicotinate

According to the process of Reference Example 43-3, the title compound was prepared from the compound of Reference Example 60-2.

LC-MS ([M+H]⁺/Rt (min)): 250.1/1.014

Reference Example 60-4 Isopropyl 6-bromo-5-(difluoromethyl)-nicotinate

To a solution of the compound of Reference Example 60-3 (500 mg) in acetonitrile (10 mL) was added bromotrimethylsilane (0.52 mL), and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (585 mg).

LC-MS ([M+H]⁺/Rt (min)): 294.0/1.035

Reference Example 60-5 Isopropyl 5-(difluoromethyl)-6-{[(4-methoxybenzyl)oxy]methyl}-nicotinate

To a solution of the compound of Reference Example 60-4 (100 mg) in 1,4-dioxane (3 mL)/water (0.3 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct (28 mg), potassium (4-methoxy)benzyloxymethyltrifluoroborate (114 mg), and cesium carbonate (222 mg), and then the mixture was stirred at 120° C. for 9.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (70 mg).

LC-MS ([M+H]⁺/Rt (min)): 366.5/1.129

¹H-NMR (400 MHz, CDCl₃): δ 9.20 (1H, s), 8.54 (1H, s), 7.27 (2H, d, J=8.7 Hz), 7.16 (1H, t, J=54.8 Hz), 6.89 (2H, d, J=8.7 Hz), 5.30 (1H, sep, J=5.9 Hz), 4.83 (2H, s), 4.52 (2H, s), 3.81 (3H, s), 1.40 (6H, d, J=5.9 Hz).

Reference Example 60-6 Isopropyl 5-(difluoromethyl)-6-(hydroxymethyl)-nicotinate

To a solution of the compound of Reference Example 60-5 (44 mg) in dichloromethane (1.5 mL) was added TFA (1.5 mL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (16 mg).

LC-MS ([M+H]⁺/Rt (min)): 246.1/0.756

Reference Example 61 Tert-butyl 5-bromo-6-chloro-nicotinate

A suspension of 5-bromo-6-hydroxy-nicotinic acid (10 g) in thionyl chloride (17 mL)/DMF (0.36 mL) was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the residue were added toluene (50 mL), N,N-diisopropylethylamine (16 mL), and tert-butanol (22 mL), and then the mixture was stirred at room temperature for 3 hours and then at 80° C. for 1 hour. DMAP (0.28 g) was added thereto, and the mixture was additionally stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium carbonate solution and water were added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution, saturated aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and then brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.85 g).

LC-MS ([M+H]⁺/Rt (min)): 292.0/1.188

Reference Example 62 Isopropyl 5-(difluoromethyl)-6-iodo-nicotinate

According to the process of Reference Example 60-4, the title compound was prepared from the compound of Reference Example 60-3 and iodotrimethylsilane.

LC-MS ([M+H]⁺/Rt (min)): 342.0/1.054

Reference Example 63 Methyl 5-(difluoromethyl)-6-iodo-nicotinate

According to the process of Reference Example 60-4, the title compound was prepared from the compound of Reference Example 43-3 and iodotrimethylsilane.

LC-MS ([M+H]⁺/Rt (min)): 314.0/0.875

Reference Example 64-1 4-Nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole

A suspension of sodium hydride (3.04 g) in DMF (15 mL) was cooled with an ice, and a solution of 4-nitroimidazole (5.66 g) in DMF (40 mL) was added thereto, and then the mixture was stirred with ice-cooling for 45 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (9.65 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. Methanol, an ice, and brine were added thereto, and the mixture was extracted with hexane/ethyl acetate (1/1) The organic layer was dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.62 g).

LC-MS ([M+H]⁺/Rt (min)): 244.1/0.927

Reference Example 64-2 1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-amine

A suspension of the compound of Reference Example 64-1 (7.84 g) and rhodium/carbon (3.92 g) in ethyl acetate (200 mL) was stirred under hydrogen atmosphere at room temperature for 10 hours. The reaction mixture was filtered through Celite®, and to the filtrate was added hydrogen chloride (4 mol/L in 1,4-dioxane, 8 mL), and then the mixture was concentrated in vacuo to give the title compound (6.22 g).

LC-MS ([M+H]⁺/Rt (min)): 214.2/0.665

Reference Example 64-3 5-(Difluoromethyl)-6-{[(4-methoxybenzyl)oxy]methyl}-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)nicotinamide

According to the process of Example 49, the title compound was prepared from the compounds of Reference Examples 64-2 and 60-5.

LC-MS ([M+H]⁺/Rt (min)): 519.4/1.105

Reference Example 64-4 5-(Difluoromethyl)-6-(hydroxymethyl)-N-(1H-imidazol-4-yl)nicotinamide

According to the process of Example 50, the title compound was prepared from the compound of Reference Example 64-3.

LC-MS ([M+H]⁺/Rt (min)): 269.1/0.322

Reference Example 65-1 N-{1-[3-(Trifluoromethyl)benzyl]-1H-imidazol-4-yl}prop-2-enamide

To a solution of the compound of Reference Example 4 (1 g) and DIEA (1.4 mL) in THF (25 mL) was added acryloyl chloride (0.32 mL) slowly. The reaction mixture was stirred at room temperature for 1.5 hours, and water was added thereto, and then the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.13 g).

LC-MS ([M+H]⁺/Rt (min)): 296.2/0.718

¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (1H, s), 7.69-7.66 (3H, m), 7.62-7.57 (2H, m), 7.33 (1H, s), 6.44 (1H, dd, J=17.1, 10.4 Hz), 6.15 (1H, dd, J=17.1, 2.4 Hz), 5.63 (1H, dd, J=10.4, 2.4 Hz), 5.27 (2H, s).

Reference Example 65-2 Methyl 5-[(1E)-3-oxo-3-({1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}amino) prop-1-en-1-yl]picolinate

To a solution of the compound of Reference Example 65-1 (60 mg) in DMF (2 mL) were added methyl 5-bromo-picolinate (53 mg), dichlorobis(tri-O-tolylphosphine)palladium (II) (16 mg), and triethylamine (0.042 mL), and the mixture was stirred at 90° C. for 3.5 hours and then at 130° C. for 2 hours. The mixture was cooled to room temperature, and water and a small amount of methanol were added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The resulting residue was purified by amino silica gel column chromatography (ethyl acetate/methanol) to give the title compound (42 mg).

LC-MS ([M+H]⁺/Rt (min)): 431.2/0.790

¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (1H, s), 8.87 (1H, s), 8.14-8.08 (2H, m), 7.71-7.56 (6H, m), 7.41 (1H, s), 7.07 (1H, d, J=15.8 Hz), 5.29 (2H, s), 3.88 (3H, s).

Reference Example 66 Ethyl (2E)-3-[6-(hydroxymethyl)pyridin-3-yl]prop-2-enoate

To a solution of 2-ethoxycarbonyl vinylboronic acid pinacol ester (361 mg) in 1,4-dioxane (15 mL)/water (1.5 mL) were added 5-bromo-2-hydroxymethylpyridine (300 mg), bis(tri-t-butylphosphine)palladium (0) (122 mg), and potassium carbonate (662 mg), and the mixture was stirred under microwave irradiation at 130° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water was added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (204 mg).

LC-MS ([M+H]⁺/Rt (min)): 208.1/0.476

Reference Example 67 Ethyl (2E)-3-[5-chloro-6-(hydroxymethyl)pyridin-3-yl]prop-2-enoate

According to the process of Reference Example 66, the title compound was prepared from the corresponding starting compound.

LC-MS ([M+H]⁺/Rt (min)): 242.1/0.719

Reference Example 68-1 6-Chloro-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]pyridazine-3-carboxamide

According to the process of Reference Example 7, the title compound was prepared from the compound of Reference Example 6 and the commercially available starting compound.

LC-MS ([M+H]⁺/Rt (min)): 368.2/0.820

Reference Example 68-2 6-Ethenyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]pyridazine-3-carboxamide

According to the process of Reference Example 20, the title compound was prepared from the compound of Reference Example 68-1.

LC-MS ([M+H]⁺/Rt (min)): 360.2/0.809

Example 1 5-(Hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}picolinamide

To a solution of Reference Example 7 (100 mg) in THF (2 mL)/methanol (1 mL) was added lithium borohydride (3 mol/L in THF, 0.08 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. To the resulting solid were added ethyl acetate (2 mL) and hexane (2 mL), and the mixture was placed in an ultrasound bath, and then the resulting solid was collected on a filter, washed with hexane/ethyl acetate (1/1, 1 mL×2), and dried at 40° C. in vacuo to give the title compound (70 mg).

LC-MS ([M+H]⁺/Rt (min)): 377.2/0733

Examples 2-3

According to the process of Example 1, the compounds of Examples 2-3 were prepared from the corresponding compound of each Reference Example.

LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 2

393.2/0.594 3

369.1/0.732

Example 4 6-[Hydroxy(²H₂)methyl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a suspension of lithium aluminum deuteride (21 mg) in THF (3 mL) was added the compound of Reference Example 8 (100 mg) with ice-cooling, and the mixture was stirred at this temperature for 30 minutes and then at room temperature for 2 hours. Lithium aluminum deuteride (11 mg) was added thereto, and the mixture was additionally stirred at room temperature for 1 hour. Water (0.040 mL), 10% aqueous sodium hydroxide solution (0.060 mL), and then water (0.12 mL) were added thereto, and the mixture was stirred at room temperature for 20 minutes. The insoluble product was removed by filtration, and the residue was washed with water, ethyl acetate/methanol (1/1), ethyl acetate, and then methanol. The filtrate was concentrated in vacuo, and to the residue were added methanol and water, and then the mixture was placed in an ultrasound bath. The resulting precipitate was collected on a filter, washed with water, and then dried at 50° C. in vacuo to give the title compound (53 mg).

LC-MS ([M+H]⁺/Rt (min)): 379.2/0.673

¹H-NMR (400 MHz, DMSO-de): δ 11.00 (1H, s), 9.01 (1H, d, J=1.8 Hz), 8.30 (1H, d, J=8.2, 1.8 Hz), 7.73-7.68 (3H, m), 7.64-7.61 (2H, m), 7.54 (1H, d, J=8.2 Hz), 7.47 (1H, d, J=1.2 Hz), 5.48 (1H, s), 5.31 (2H, s).

Example 5 6-(2-Hydroxypropan-2-yl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Reference Example 8 (70 mg) in THF (5 mL) was added methylmagnesium bromide (0.97 mol/L in THF, 0.89 mL), and the mixture was stirred at room temperature for 20 hours. Methylmagnesium bromide (0.97 mol/L in THF, 0.45 mL) was added thereto, and the mixture was additionally stirred for 5.5 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (10 mg).

LC-MS ([M+H]⁺/Rt (min)): 405.2/0.742

¹H-NMR (400 MHz, DMSO-d₆): δ 10.97 (1H, s), 8.99 (1H, s), 8.27 (1H, d, J=8.2 Hz), 7.77-7.61 (6H, m), 7.47 (1H, s), 5.31-5.30 (3H, m), 1.44 (6H, s).

Example 6 6-(1-Hydroxyethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

According to the process of Example 5, the title compound was prepared from the compound of Reference Example 48.

LC-MS ([M+H]⁺/Rt (min)): 391.2/0.717

¹H-NMR (400 MHz, DMSO-d₆): δ 10.98 (1H, s), 9.00 (1H, d, J=1.8 Hz), 8.29 (1H, dd, J=8.3, 1.8 Hz), 7.73-7.72 (2H, m), 7.70-7.68 (1H, m), 7.64-7.61 (2H, m), 7.57 (1H, d, J=8.3 Hz), 7.47 (1H, d, J=1.2 Hz), 5.46 (1H, d, J=4.9 Hz), 5.30 (2H, s), 4.75 (1H, qd, J=6.7, 4.9 Hz), 1.36 (3H, d, J=6.7 Hz).

Examples 7-9

According to the process of Reference Example 7, the compounds of Examples 7-9 were prepared from the corresponding compounds of each Reference Example.

LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 7

383.2/0.729 8

369.1/0.690 9

391.2/0.773

Example 10 6-(Hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide

To a solution of methyl 6-(hydroxymethyl)-nicotinate (0.924 g) in THF (22 mL) was added 5 mol/L aqueous potassium hydroxide solution (2.2 ml). The mixture was stirred at room temperature overnight, concentrated in vacuo to remove the solvent, and then dried in vacuo. To a solution of the resulting solid in DMF (25 mL) were added the compound of Reference Example 6 (1.61 g), HATU (2.52 g), and diisopropylethylamine (2.38 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were then added saturated aqueous sodium hydrogen carbonate solution and water, and the resulting precipitate was collected on a filter. The resulting filter cake was washed with water/acetonitrile and then ethyl acetate, and dried in vacuo to give the title compound (1.375 g).

LC-MS ([M+H]⁺/Rt (min)): 363.1/0.66

¹H-NMR (400 MHz, DMSO-d₆): δ 11.00 (1H, s), 9.01 (1H, d, J=1.8 Hz), 8.30 (1H, dd, J=7.9, 1.8 Hz), 7.69 (1H, d, J=1.2 Hz), 7.54 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=1.2 Hz), 7.38-7.30 (2H, m), 5.52 (1H, t, J=6.1 Hz), 5.18 (2H, s), 4.60 (2H, d, J=6.1 Hz).

Examples 11-21

According to the process of Example 10, the compounds of Examples 11-21 were prepared from the corresponding compounds of each Reference Example.

Examples chemical structural formula instrumental analysis data 11

LC-MS: [M + H]⁺/Rt (min): 343.2/0.611 12

¹H-NMR (400 MHz, DMSO-d₆): 10.99 (1H, s), 9.01 (1H, d, J = 1.8 Hz), 8.30 (1H, dd, J = 8.5, 1.8 Hz), 7.73-7.72 (2H, m), 7.70-7.68 (1H, m), 7.64-7.59 (2H, m), 7.54 (1H, d, J = 8.5 Hz), 7.47 (1H, d, J = 1.2 Hz), 5.51 (1H, t, J = 6.1 Hz), 5.31 (2H, s), 4.60 (2H, d, J = 6.1 Hz). LC-MS: [M + H]⁺/Rt (min): 377.3/0.672 13

LC-MS: [M + H]⁺/Rt (min): 377.2/0.637 14

LC-MS: [M + H]⁺/Rt (min): 403.3/0.712 15

¹H-NMR (400 MHz, DMSO-d₆): 9.88 (1H, s), 9.06 (1H, s), 8.22-8.18 (1H, m), 7.72 (1H, d, J = 8.4 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.54-7.44 (4H, m), 7.39 (1H, d, J = 8.0 Hz), 5.92 (1H, s), 5.64 (1H, s), 5.61 (2H, s), 4.61 (2H, s). LC-MS: [M + H]⁺/Rt (min): 403.3/0.745 16

¹H-NMR (400 MHz, DMSO-d₆): 11.03 (1H, s), 9.03 (1H, d, J = 1.8 Hz), 8.31 (1H, dd, J = 7.9, 2.4 Hz), 7.69 (1H, d, J = 1.8 Hz), 7.51-7.48 (2H, m), 7.38-7.31 (2H, m), 5.18 (2H, s), 4.58 (2H, s), 3.56 (2H, q, J = 6.7 Hz), 1.19 (3H, t, J = 6.7 Hz). LC-MS: [M + H]⁺/Rt (min): 391.3/0.82 17

¹H-NMR (400 MHz, DMSO-d₆): 11.27 (1H, s), 9.17 (1H, d, J = 1.8 Hz), 8.54 (1H, d, J = 1.8 Hz), 7.75-7.73 (2H, m), 7.70-7.68 (1H, m), 7.64-7.61 (2H, m), 7.49 (1H, d, J = 1.2 Hz), 7.42 (1H, t, J = 54.3 Hz), 5.61 (1H, t, J = 5.8 Hz), 5.31 (2H, s), 4.75 (2H, d, J = 5.8 Hz). LC-MS: [M + H]⁺/Rt (min): 427.2/0.787 18

¹H-NMR (400 MH, DMSO-d₆): 11.27 (1H, s), 9.17 (1H, s), 8.54 (1H, s), 7.71 (1H, s), 7.51 (1H, s), 7.42 (1H, t, J = 54.8 Hz), 7.37-7.33 (2H, m), 5.61 (1H, t, J = 5.8 Hz), 5.19 (2H, s), 4.75 (2H, d, J = 5.8 Hz). LC-MS: [M + H]⁺/Rt (min): 367.2/0.735 19

LC-MS: [M + H]⁺/Rt (min): 378.2/0.713 20

LC-MS: [M + H]⁺/Rt (min): 378.2/0.713 21

¹H-NMR (400 MHz, DMSO-d₆): 10.97 (1H, s), 7.73-7.68 (3H, m), 7.64-7.57 (2H, m), 7.45 (1H, s), 6.81 (1H, s), 5.73 (1H, t, J = 5.8 Hz), 5.30 (2H, s), 4.60 (2H, d, J = 5.8 Hz). LC-MS: [M + H]⁺/Rt (min): 367.2/0.735

Example 22 N-[6-(Hydroxymethyl)pyridin-3-yl]-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide

To a solution of the compound of Reference Example 49-2 (138 mg) and the compound of Reference Example 50 (141 mg) in DMF (15 mL) were added EDCI HCl (124 mg), HOBt (87 mg), and N,N-diisopropylethylamine (0.188 mL), and the mixture was stirred at 80° C. for 6 hours. To the reaction mixture were then added water and aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo. The resulting residue was dissolved in methanol (5 mL), and 2 mol/L hydrochloric acid/methanol (0.81 mL) was added thereto, and then the mixture was stirred at 40° C. for 5 hours. To the reaction mixture was added water and then aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (86.4 mg).

LC-MS ([M+H]⁺/Rt (min)): 363.2/0.640

¹H-NMR (400 MHz, DMSO-d_(F)): δ 10.06 (1H, s), 8.84 (1H, s), 8.19-8.14 (1H, m), 7.97-7.95 (2H, m), 7.42-7.34 (3H, m), 5.31-5.26 (1H, m), 5.24 (2H, s), 4.48 (2H, d, J=4.8 Hz).

Example 23 N-[2-(hydroxymethyl)quinolin-6-yl]-1-(3,4,5-trifluorobenzyl)-1H-imidazole-4-carboxamide

According to the process of Example 22, the title compound was prepared from the compounds of Reference Examples 49-2 and 51.

LC-MS ([M+H]⁺/Rt (min)): 413.3/0.673

¹H-NMR (400 MHz, DMSO-d₆): δ 10.13 (1H, s), 8.49 (1H, d, J=2.0 Hz), 8.24 (1H, d, J=9.2 Hz), 8.04 (1H, dd, J=9.2, 2.0 Hz), 8.00 (1H, s), 7.98 (1H, s), 7.85 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=8.8 Hz), 7.44-7.38 (2H, m), 5.50-5.46 (1H, m), 5.25 (2H, s), 4.60 (2H, d, J=5.6 Hz).

Example 24 6-(Aminomethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide ditrifluoroacetate

According to the process of Reference Example 45-2, the title compound was prepared from the compound of Reference Example 39-2.

LC-MS ([M+H]⁺/Rt (min)): 376.2/0.597

Example 25 6-[(Acetylamino)methyl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Example 24 (30 mg) in THF (1 mL) were added triethylamine (0.111 mL) and anhydrous acetic acid (0.038 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (28 mg).

LC-MS ([M+H]⁺/Rt (min)): 418.3/0.669

¹H-NMR (400 MHz, DMSO-d₆): δ 11.02 (1H, s), 9.01 (1H, d, J=1.8 Hz), 8.48 (1H, t, J=6.1 Hz), 8.26 (1H, dd, J=8.3, 1.8 Hz), 7.73-7.68 (3H, m), 7.64-7.59 (2H, m), 7.46 (1H, s), 7.35 (1H, d, J=8.3 Hz), 5.30 (2H, s), 4.37 (2H, d, J=6.1 Hz), 1.90 (3H, s).

Example 26 6-[(Methylamino)methyl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Reference Example 58 (155 mg) in DMF (1 mL) were added potassium carbonate (59 mg) and thiophenol (30 μL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added diethyl ether, and the organic layer was extracted with 0.1 mol/L hydrochloric acid. To the resulting aqueous layer was added saturated aqueous sodium hydrogen carbonate solution to adjust pH to 9, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and then the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (93 mg).

LC-MS ([M+2H]²⁺/Rt (min)): 195.7/0.628

Examples 27-29

According to the process of Reference Example 32, the compounds of Examples 27-29 were prepared from the corresponding compounds of each Reference Example.

LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 27

425.3/0.697 28

441.2/0.791 29

485.2/0.742

Example 30

5-Fluoro-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a solution of the compound of Example 27 (51 mg) in THF (2 mL)/water (1 mL) was added sodium periodate (77 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. To a solution of the resulting residue in methanol (1 mL) was added sodium borohydride (4 mg), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was stirred at room temperature for 5 minutes, and then concentrated in vacuo. To the residue was added water, and the mixture was placed in an ultrasound bath, and then the precipitate was collected on a filter. The resulting filter cake was washed with water and methanol, and then dried at 50° C. in vacuo to give the title compound (37 mg).

LC-MS ([M+H]⁺/Rt (min)): 395.3/0.739

Examples 31-39

According to the process of Example 30, the compounds of Examples 31-39 were prepared from the compounds of Examples 28-29 and the corresponding compounds of each Reference Example.

Examples chemical structural formula instrumental analysis data 31

¹H-NMR (400 MHz, DMSO-d₆): 11.17 (1H, s), 9.01 (1H, d, J = 1.8 Hz), 8.39 (1H, d, J = 1.8 Hz), 7.76-7.68 (3H, m), 7.64-7.59 (2H, m), 7.48 (1H, s), 5.34 (1H, t, J = 6.1 Hz), 5.31 (2H, s), 4.67 (2H, d, J = 6.1 Hz). LC-MS: [M + H]⁺/Rt (min): 411.2/0.791 32

LC-MS: [M + H]⁺/Rt (min): 455.2/0.806 33

LC-MS: [M + H]⁺/Rt (min): 407.3/0.711 34

LC-MS: [M + H]⁺/Rt (min): 391.2/0.646 35

LC-MS: [M + H]⁺/Rt (min): 391.2/0.669 36

LC-MS: [M + H]⁺/Rt (min): 411.2/0.743 37

LC-MS: [M + H]⁺/Rt (min): 367.2/0.681 38

LC-MS: [M + H]⁺/Rt (min): 441.1/0.769 39

¹H-NMR (400 MHz, DMSO-d₆): 10.97 (1H, s), 8.87 (1H, d, J = 1.8 Hz), 8.10 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 1.2 Hz), 7.48 (1H, d, J = 1.2 Hz), 7.38-7.31 (2H, m), 5.18 (2H, s), 5.11 (1H, t, J = 5.5 Hz), 4.60 (2H, d, J = 5.5 Hz), 2.35 (3H, s). LC-MS: [M + H]⁺/Rt (min): 377.2/0.631

Example 40 2-(Hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}-1,3-thiazole-5-carboxamide

To a solution of the compound of Reference Example 27 (211 mg) in acetone (5 mL)/water (2.5 mL) were added osmium tetroxide (2.5 wt % in tert-butanol, 0.525 mL) and sodium periodate (358 mg), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added saturated aqueous sodium thiosulfate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was roughly purified by silica gel column chromatography (chloroform/methanol). To the resulting compound were added methanol (2 mL) and sodium borohydride (3 mg), and then the mixture was stirred at room temperature for 18.5 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution and water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (8 mg).

LC-MS ([M+H]⁺/Rt (min)): 383.2/0.705

¹H-NMR (400 MHz, DMSO-d₆): δ 9.77 (1H, s), 8.31 (1H, s), 7.72-7.71 (2H, m), 7.70-7.67 (1H, m), 7.62-7.60 (2H, m), 7.40 (1H, d, J=1.8 Hz), 6.19 (1H, t, J=5.8 Hz), 5.30 (2H, s), 4.77 (2H, d, J=5.8 Hz).

Example 41 5-Chloro-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide

According to the process of Example 40, the title compound was prepared from the compound of Reference Example 30.

LC-MS ([M+H]⁺/Rt (min)): 397.2/0.750

Example 42 6-(Hydroxymethyl)-5-methyl-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

According to the process of Reference Example 31, the title compound was prepared from the compound of Example 32.

LC-MS ([M+H]⁺/Rt (min)): 391.3/0.671

¹H-NMR (400 MHz, DMSO-de): δ 10.96 (1H, s), 8.86 (1H, d, J=1.8 Hz), 8.10 (1H, d, J=1.8 Hz), 7.73-7.68 (3H, m), 7.64-7.59 (2H, m), 7.46 (1H, d, J=1.8 Hz), 5.31 (2H, s), 5.12 (1H, t, J=5.8 Hz), 4.60 (2H, d, J=5.8 Hz), 2.35 (3H, s).

Example 43 5-Ethenyl-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

According to the process of Reference Example 20, the title compound was prepared from the compound of Example 32.

LC-MS ([M+H]⁺/Rt (min)): 403.3/0.744

Example 44 5-Ethyl-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a suspension of platinum oxide (30 mg) in ethyl acetate (2 mL)/methanol (1 mL) was added the compound of Example 43 (27 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol) to give the title compound (16 mg).

LC-MS ([M+H]⁺/Rt (min)): 405.3/0.708

Example 45 5-Amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide

To a suspension of the compound of Reference Example 41-6 (13 mg) in THF (0.5 mL)/methanol (0.5 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.031 mL), and the mixture was stirred at 60° C. for 3 hours and then at 90° C. for 6.5 hours. The reaction mixture was cooled to room temperature, and water was added thereto, and then the mixture was stirred at room temperature for 5 minutes. The resulting solid was collected on a filter, washed with water, and dried at 50° C. in vacuo to give the title compound (7 mg)

LC-MS ([M+H]⁺/Rt (min)): 392.2/0.647

¹H-NMR (400 MHz, DMSO-d₆): δ 10.79 (1H, s), 8.29 (1H, d, J=1.8 Hz), 7.72-7.68 (3H, m), 7.64-7.581 (2H, m), 7.43 (1H, d, J=1.2 Hz), 7.42 (1H, d, J=1.8 Hz), 5.36 (2H, s), 5.30 (2H, s), 5.18 (1H, t, J=5.5 Hz), 4.52 (2H, d, J=5.5 Hz)

Example 46 5-Amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide

According to the process of Example 45, the title compound was prepared from the compound of Reference Example 42.

LC-MS ([M+H]⁺/Rt (min)): 378.2/0.603

Example 47 4-(Hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,3-thiazole-2-carboxamide

To the compound of Reference Example 46-2 (219 mg) was added hydrogen chloride (2 mol/L in methanol, 2 mL), and the mixture was added at room temperature for 1 hour. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate, and then the mixture was stirred at room temperature for 10 minutes. The resulting precipitate was collected on a filter, washed with water and hexane, and then dried at 50° C. in vacuo to give the title compound (84 mg).

LC-MS ([M+H]⁺/Rt (min)): 383.2/0.769

Example 48 5-(Hydroxymethyl)-4-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]-1,3-thiazole-2-carboxamide

According to the process of Example 47, the title compound was prepared from the compound of Reference Example 47.

LC-MS ([M+H]⁺/Rt (min)): 383.2/0.743

Example 49 5-(Difluoromethyl)-6-{[(4-methoxybenzyl)oxy]methyl}-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide

To a solution of the compound of Reference Example 60-5 (2.49 g) in methanol (25 mL) was added 2 mol/L aqueous sodium hydroxide solution (6.8 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 4 mol/L hydrochloric acid (2.1 mL) to adjust pH to 8. The reaction mixture was concentrated in vacuo, and to a suspension of the resulting residue in THF (30 mL) were added DIEA (1.43 mL) and diphenyl chlorophosphate (1.70 mL), and then the mixture was stirred for 2 hours. DIEA (1.43 mL) and diphenyl chlorophosphate (1.70 mL) were added thereto, and the mixture was additionally stirred for 1 hour. DIEA (2.86 mL) and the compound of Reference Example 6 (1.97 g) were added thereto, and the mixture was stirred at room temperature for 20 hours. 2 mol/L aqueous sodium hydroxide solution (10 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. 2 mol/L aqueous sodium hydroxide solution (5 mL) was added thereto, and the mixture was additionally stirred for 1.5 hours. Methanol (15 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol) to give the title compound (1.88 g).

LC-MS ([M+H]⁺/Rt (min)): 534.3/1.021

Example 50 5-(Difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide

To a solution of the compound of Example 49 (1.88 g) in chloroform (10 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added TFA (3 mL), and the mixture was additionally stirred for 3 hours. The reaction mixture was concentrated in vacuo, and to the residue were added water and saturated aqueous sodium carbonate solution, and then the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate solution and brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.53 g).

¹H-NMR (400 MHz, DMSO-d₆): δ 11.27 (1H, s), 9.17 (1H, s), 8.54 (1H, s), 7.71 (1H, s), 7.51 (1H, s), 7.42 (1H, t, J=54.8 Hz), 7.37-7.33 (2H, m), 5.61 (1H, t, J=5.8 Hz), 5.19 (2H, s), 4.75 (2H, d, J=5.8 Hz).

LC-MS ([M+H]⁺/Rt (min)): 413.2/0.751

Examples 51-52

According the process of Example 49, the compounds of Examples 51-52 were prepared from the compound of Reference Example 4 and each corresponding starting compound.

LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 51

403.3/0.678 52

437.2/0.782

Example 53 (2E)-3-[6-(2-Hydroxypropan-2-yl)pyridin-3-yl]-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}prop-2-enamide

To a solution of the compound of Reference Example 65-2 (30 mg) in THF (2 mL) was added methylmagnesium bromide (0.97 mol/L in THF, 0.36 mL), and the mixture was stirred at room temperature for 1.5 hours. Methylmagnesium bromide (0.97 mol/L in THF, 0.36 mL) was added thereto, and the mixture was additionally stirred at room temperature for 16 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (13 mg).

LC-MS ([M+H]⁺/Rt (min)): 431.3/0.722

¹H-NMR (400 MHz, DMSO-d₆): δ 10.62 (1H, s), 8.64 (1H, s), 7.92 (1H, dd, J=8.2, 2.1 Hz), 7.70-7.57 (6H, m), 7.50 (1H, d, J=15.9 Hz), 7.38 (1H, s), 6.92 (1H, d, J=15.9 Hz), 5.29 (2H, s), 5.25 (1H, s), 1.43 (6H, s).

Examples 54-55

According to the process of Reference Example 1, the compounds of Examples 54-55 were prepared from the compound of Reference Example 64-4 and each corresponding starting compound.

LC-MS: Examples chemical structural formula [M + H]⁺/Rt (min) 54

395.2/0.698 55

393.2/0.732

Examples 56-84

According to the process of Reference Example 1, the compounds of Examples 56-84 were prepared from the compound of Reference Example 64-4 and each corresponding starting compound.

LC-MS: [M + H]⁺/ Examples Q¹—W¹— Rt (min) 56

359.2/0.672 57

445.3/0.833 58

437.2/0.785 59

373.3/0.764 60

445.3/0.840 61

411.2/0.810 62

455.2/0.837 63

373.0/0.745 64

389.3/0.697 65

457.3/0.849 66

411.2/0.796 67

455.2/0.815 68

365.2/0.776 69

451.3/0.906 70

441.3/0.874 71

427.2/0.852 72

379.3/0.870 73

443.3/0.847 74

445.3/0.847 75

427.2/0.866 76

455.2/0.819 77

419.3/0.715 78

411.2/0.802 79

395.2/0.739 80

473.1/0.875 81

360.2/0.416 82

417.2/0.788 83

441.3/0.828 84

409.3/0.817

Example 85 6-(Hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]pyridazine-3-carboxamide

According to the process of Example 40, the title compound was prepared from the compound of Reference Example 68-2.

LC-MS ([M+H]⁺/Rt (min)): 364.2/0.706

Test Example 1: Inhibition of Sphere-Forming Ability of Cancer Cells

The reliable methods established for measuring the self-renewal ability of cells which is one of the CSC's properties include a method for measuring the sphere-forming ability of cancer cells in non-adherent condition in the absence of serum (Cancer Res 65, 5506-5511 (2005)). HCT-116 cells were available from the American Type Culture Collection (ATCC). HCT-116 cells were cultured at 37° C. and 5% CO₂ using the McCoy's 5a medium containing 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. HCT-116 cells were seeded in a 384 Well Black Clear Bottom Ultra-Low Attachment Microplate (Corning Cat. No. 3827) in an amount of 350-800 cells/well using the DMEM/F12 medium containing 2% B27 supplement (GIBCO), 20 ng/mL epidermal growth factor (EGF) (peprotech), 10 ng/mL basic fibroblast growth factor (bFGF) (peprotech), 5 μg/mL insulin (Sigma), and 1% penicillin/streptomycin. The test compounds were added into each well to adjust the final concentration of DMSO to 0.1%, and the cells were cultured for 4 days. The number of viable cells in each well was then measured with CellTiter-Glo® Luminescent Cell Viability Assay (Promega) to calculate the concentration of each test compound for 50% inhibition of cell proliferation (Sphere IC₅₀ value; μmol/L).

The experiment of Test Example 1 was performed for the compounds of each Example. The concentrations of each test compound for 50% inhibition of cell profeliration (Sphere IC₅₀ value; μmol/L) are shown in the following Table.

Examples IC₅₀ (μmol/L) 1 0.030 2 0.629 3 <0.01 4 <0.01 5 8.400 6 3.650 7 0.024 8 0.077 9 5.035 10 0.007 11 0.056 12 <0.01 13 0.675 14 6.039 15 0.710 16 0.892 17 <0.01 18 <0.01 19 0.070 20 0.053 21 0.653 22 <0.01 23 0.079 24 0.061 25 4.483 26 0.824 27 0.695 28 0.847 29 0.633 30 0.069 31 <0.01 32 <0.01 33 9.795 34 7.394 35 3.763 36 0.074 37 0.238 38 0.061 39 <0.01 40 0.122 41 0.051 42 <0.01 43 5.597 44 0.758 45 0.029 46 0.010 47 0.669 48 0.095 51 0.07 52 0.05 53 7.20 54 0.148 55 0.075 56 0.430 57 <0.010 58 0.070 59 0.090 60 0.030 61 <0.010 62 <0.010 63 0.690 64 0.090 65 0.630 66 0.070 67 0.040 68 0.280 69 0.070 70 <0.010 71 <0.010 72 0.810 73 0.080 74 0.380 75 <0.010 76 0.050 78 0.050 79 0.080 82 0.720 83 0.700 85 0.020

Test Example 2: Test for Inhibiting Sphere-Forming Ability of Cancer Cells (in the Presence of BSA)

HCT-116 cells were available from the American Type Culture Collection (ATCC). HCT-116 cells were cultured at 37° C. and 5% CO₂ using the McCoy's 5a medium containing 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. HCT-116 cells were seeded in a 384 Well Black Clear Bottom Ultra-Low Attachment Microplate (Corning Cat. No. 3827) in an amount of 350-800 cells/well using the DMEM/F12 medium containing 2′ B27 supplement (GIBCO), 20 ng/mL epidermal growth factor (EGF) (peprotech), 10 ng/mL basic fibroblast growth factor (bFGF) (peprotech), 5 μg/mL insulin (Sigma), 5% bovine serum albumin (BSA), and 1% penicillin/streptomycin. The test compounds were added into each well to adjust the final concentration of DMSO to 0.1%, and the cells were cultured for 4 days. The number of viable cells in each well was then measured with CellTiter-Glo® Luminescent Cell Viability Assay (Promega) to calculate the concentration of each test compound for 50% inhibition of cell proliferation (Sphere IC₅₀ value; μmol/L).

The experiment of Test Example 2 was performed for the compounds of each Example. The concentrations of each test compound for 50% inhibition of cell profeliration (Sphere IC₅₀ value; μmol/L) are shown in the following Table.

Examples IC₅₀ (μmol/L) 1 0.350 2 0.605 3 0.051 4 0.061 6 6.970 7 0.520 8 0.578 10 0.007 12 0.060 13 0.735 15 5.766 16 1.446 17 0.057 18 0.053 19 0.403 20 0.313 21 0.767 22 <0.01 23 0.084 24 0.696 25 4.968 27 6.230 28 4.585 29 3.501 30 0.563 31 <0.01 32 0.068 35 6.106 36 0.481 37 0.451 38 0.081 39 <0.01 40 0.629 41 0.059 42 0.060 43 6.511 44 5.112 45 0.059 46 0.057 47 5.455 48 0.571 51 0.63 52 0.41 53 >10 54 0.603 55 0.619 56 0.540 57 0.050 58 0.080 59 0.100 60 0.060 61 0.030 62 0.050 63 0.600 64 0.290 65 0.660 66 0.060 67 0.070 68 0.540 69 0.330 70 0.060 71 0.060 72 0.670 73 0.080 74 0.670 75 0.050 76 0.060 78 0.060 79 0.060 82 0.470 83 0.580 85 0.030

Test Example 3. Pharmacokinetic Assay in Mouse

A 7-week-old mouse (BALB/cAnNCrlCrlj, female, CHARLES RIVER LABORATORIES JAPAN, INC.) receives single oral administration of each compound suspended in 0.5% methylcellulose solution in a dose of 10 mg/kg or 100 mg/kg. Blood is collected from the mouse 0.5, 1, 2, 4, 8 and 24 hours after the administration, and plasma from the blood is collected by centrifugation. The area under the plasma concentration-time curve (AUC) is calculated on the basis of the concentration changes to calculate the bioavailability of each compound according to the following formula:

Bioavailabity (%)=AUC after oral administration/AUC after intravenous administration×100

Plasma is deproteinized by adding methanol at the final concentration of 80%, centrifuging the methanol solution, and filtrating the contrifuged solution, and then the present compound in the deproteinized plasma is detected and quantified with an LC-MS/MS (API4000, AB SCIEX). When the present compound is quantified, a calibration curve is prepared based on the mouse plasma added with a given amount of the compound. Bezafibrate is used as internal standard.

Test Example 4. Anti-Tumor Effect to HCT-116 Tumor-Bearing Mouse

The present compound can be used to evaluate the anti-tumor effect thereof. A 4 to 7-week-old nude mouse (BALB/cAnNCrj-nu/nu, female, CHARLES RIVER LABORAORATORIES JAPAN, INC.) received intradermal transplantation of HCT-116 cells (ATCC) in an amount of 3×10⁶ cells/mouse around the ventral portion. The engraftment of HCT-116 cells was observed 5 to 14 days after the transplantation, and then each compound suspended in a solvent such as 0.5% methylcellulose solution was orally administrated to the mouse in a dose of 1 to 100 mg/kg one to twice daily. The tumor volume was measured over time after the administration to evaluate the effect for reducing the tumor volume by the administration of each compound. The tumor volume can be calculated from the minor axis and the major axis of the tumor measured with a digital caliper (Mitutoyo) according to the following formula:

Tumor volume [mm³]=0.5×minor axis [mm]×(major axis [mm])²

The tumor volume in control administration group treated with only a solvent such as 0.5% methylcellulose solution was compared with that of the present compound administration group, and T/C value was calculated according the following formula to evaluate the anti-tumor effect of the present compound.

T/C(%)=(the tumor volume at the end of administration in the present compound administration group−the tumor volume at the start of administration in the present compound administration group)/(the tumor volume at the end of administration in the control administration group−the tumor volume at the start of administration in the present compound administration group)×100

The T/C values (%) of the present compound on each dosage and administration period in the HCT-116 tumor-bearing mouse are shown below.

dosage administration T/C Examples (mg/kg) period (day) (%) 12 100 16 49 17 30 17 74 17 100 17 75 18 30 17 63 18 100 17 54 39 30 17 79 39 100 17 65 45 30 17 90 45 100 17 81 46 30 17 91 46 100 17 91

INDUSTRIAL APPLICABILITY

The present compound has a potent inhibitory effect on sphere-forming ability of cancer cells, and is useful as an orally-available anti-tumor agent. 

1. A compound selected from the group consisting of: 5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide; 5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide; 6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide; 5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide; and 5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 wherein the compound is 5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide, or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 1 wherein the compound is 5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 1 wherein the compound is 6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 1 wherein the compound is 5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide, or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1 wherein the compound is 5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 7. A method for treating cancer which comprises administering a therapeutically effective amount of a compound selected from the group consisting of: 5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide; 5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide; 6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide; 5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide; and 5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof to a patient in need thereof.
 8. The method of claim 7 wherein the compound is 5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide, or a pharmaceutically acceptable salt thereof.
 9. The method of claim 7 wherein the compound is 5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 10. The method of claim 7 wherein the compound is 6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 11. The method of claim 7 wherein the compound is 5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide, or a pharmaceutically acceptable salt thereof.
 12. The method of claim 7 wherein the compound is 5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof.
 13. The method of claim 7 which comprises inhibiting the sphere-forming ability of cancer cells.
 14. A method for inhibiting the sphere-forming ability of cancer cells, which comprises administering a therapeutically effective amount of a compound selected from the group consisting of: 5-(difluoromethyl)-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide; 5-(difluoromethyl)-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide; 6-(hydroxymethyl)-5-methyl-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide; 5-amino-6-(hydroxymethyl)-N-{1-[3-(trifluoromethyl)benzyl]-1H-imidazol-4-yl}nicotinamide; and 5-amino-6-(hydroxymethyl)-N-[1-(3,4,5-trifluorobenzyl)-1H-imidazol-4-yl]nicotinamide, or a pharmaceutically acceptable salt thereof to a patient in need thereof. 